P19-2015-89 Н. А. КоЛтоВая ЦИКЛИН-ЗАВИСИМАЯ

P19-2015-89
. . Šμ²Éμ¢ Ö ∗
–ˆŠ‹ˆ-‡‚ˆ‘ˆŒŸ Šˆ‡ CDK1/CDC28
ˆ Š’‹œ›… ’—Šˆ •†„…ˆŸ
Š‹…’—ƒ –ˆŠ‹ (—…Š‰’›)
¶· ¢²¥´μ ¢ ¦Ê·´ ² ®¨μ̨³¨Ö¯
∗
E-mail: koltovaya@jinr.ru
Šμ²Éμ¢ Ö . .
–¨±²¨´-§ ¢¨¸¨³ Ö ±¨´ § CDK1/CDC28 ¨ ±μ´É·μ²Ó´Ò¥ Éμα¨
¶·μÌ즤¥´¨Ö ±²¥Éμδμ£μ ͨ±² (Î¥±¶μ°´ÉÒ)
P19-2015-89
·ÊÏ¥´¨Ö ͨ±² ¤¥²¥´¨Ö ±²¥Éμ± ¢Ò§Ò¢ ÕÉ £¥´¥É¨Î¥¸±ÊÕ ´¥¸É ¡¨²Ó´μ¸ÉÓ,
Ö¢²ÖÕÐÊÕ¸Ö ¶·¨Î¨´μ° § ¡μ²¥¢ ´¨° Î¥²μ¢¥± , ¢ Éμ³ Î¨¸²¥ ´¥μ¶² ¸É¨Î¥¸±μ°
É· ´¸Ëμ·³ ͨ¨ ±²¥Éμ±. Œ¥Ì ´¨§³ ±μ´É·μ²Ö ¶· ¢¨²Ó´μ¸É¨ ¶·μÌ즤¥´¨Ö ±²¥Éμδμ£μ ͨ±² ´ ¨¡μ²¥¥ Ìμ·μÏμ ¨§ÊÎ¥´ Ê ¤·μ¦¦¥° Saccharomyces cerevisiae, Ê ±μÉμ·ÒÌ ¢¶¥·¢Ò¥ ¡Ò² μ¡´ ·Ê¦¥´ Î¥±¶μ°´É-±μ´É·μ²Ó. ‚ ´ ¸ÉμÖÐ¥¥ ¢·¥³Ö ¨¤¥´É¨Ë¨Í¨·μ¢ ´μ ¡μ²ÓÏμ¥ ±μ²¨Î¥¸É¢μ ±μ³¶μ´¥´Éμ¢ ÔÉμ£μ ¶·μÍ¥¸¸ . ‚ ¤ ´´μ³ μ¡§μ·¥
· ¸¸³ É·¨¢ ¥É¸Ö ÊÎ ¸É¨¥ Í¥´É· ²Ó´μ° ±¨´ §Ò CDK1/CDC28, ·¥£Ê²¨·ÊÕÐ¥° ¤¥²¥´¨¥ ±²¥É±¨, ¢ Î¥±¶μ°´É-±μ´É·μ²¥ ¢ · §´ÒÌ Ë § Ì ±²¥Éμδμ£μ ͨ±² .
¡μÉ ¢Ò¶μ²´¥´ ¢ ‹ ¡μ· Éμ·¨¨ · ¤¨ Í¨μ´´μ° ¡¨μ²μ£¨¨ ˆŸˆ.
·¥¶·¨´É ¡Ñ¥¤¨´¥´´μ£μ ¨´¸É¨ÉÊÉ Ö¤¥·´ÒÌ ¨¸¸²¥¤μ¢ ´¨°. „Ê¡´ , 2015
Koltovaya N. A.
Cyclin-Dependent Kinase CDK1/CDC28 and Checkpoints
P19-2015-89
The genetic instability induced by defects in the cell cycle progression contributes to different human diseases, particularly neoplastic transformation. The
control mechanisms of correct cell cycle progression are the most studied in the
yeast Saccharomyces cerevisiae, in which checkpoint was ˇrst discovered. Many
components of these processes have been identiˇed by now. Here, the role of the
central kinase of cell cycle CDK1/CDC28 is considered in checkpoint in different
phases.
The investigation has been performed at the Laboratory of Radiation Biology,
JINR.
Preprint of the Joint Institute for Nuclear Research. Dubna, 2015
¢¸¥Ì ¸É ¤¨ÖÌ ±²¥Éμδμ£μ ͨ±² ¸ÊÐ¥¸É¢ÊÕÉ ±μ´É·μ²Ó´Ò¥ Éμα¨, ¢ ±μÉμ·ÒÌ ¶·μ¢¥·Ö¥É¸Ö ¶· ¢¨²Ó´μ¸ÉÓ ¶·μÌ즤¥´¨Ö ±²¥Éμδμ£μ ͨ±² ¨, ¢ Î ¸É´μ¸É¨, Í¥²μ¸É´μ¸ÉÓ £¥´μ³ . ·¨ ´ ·ÊÏ¥´¨¨ ¶·μÍ¥¸¸ ¤¥²¥´¨Ö ¨²¨ ¶μ¢·¥¦¤¥´¨¨ „Š ¢ ÔÉ¨Ì Éμα Ì ±É¨¢¨·Ê¥É¸Ö ¸¶¥Í¨ ²Ó´Ò° ³¥Ì ´¨§³, ´ §¢ ´´Ò°
Î¥±¶μ°´Éμ³, ±μÉμ·Ò° μ¸ÊÐ¥¸É¢²Ö¥É μ¸É ´μ¢±Ê ¤¥²¥´¨Ö ±²¥É±¨ ¨ ʸɷ ´¥´¨¥ ´ ·ÊÏ¥´¨°. ’ ±, Î¥±¶μ°´É ¶μ¢·¥¦¤¥´¨° „Š ¶μ³¨³μ μ¸É ´μ¢±¨ ±²¥Éμδμ£μ ¤¥²¥´¨Ö μ¡¥¸¶¥Î¨¢ ¥É ·¥¶ · Í¨Õ „Š [1], ±μ´É·μ²¨·Ê¥É ¤²¨´Ê É¥²μ³¥· [2], ±É¨¢¨·Ê¥É É· ´¸±·¨¶Í¨Õ [3] ¨ § ¶Ê¸± ¥É ¶μ¶Éμ§ [4]. ‘¨£´ ²¶¥·¥¤ ÕШ° ± ¸± ¤ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö Î¥±¶μ°´Éμ¢ ¸μ¸Éμ¨É ¨§ ´¥¸±μ²Ó±¨Ì
ÔÉ ¶μ¢ (·¨¸Ê´μ±).
‚´ Î ²¥ Ëμ·³¨·Ê¥É¸Ö ¸¨£´ ², ¨ ¶μ¢·¥¦¤¥´¨Ö ʧ´ ÕÉ¸Ö ¡¥²± ³¨-¸¥´¸μ· ³¨. ‡ É¥³ ¸ ¶μ³μÐÓÕ ¤ ¶Éμ·μ¢ ± ¶μ¢·¥¦¤¥´¨Ö³ ¤μ¸É ¢²ÖÕÉ¸Ö ¸¥´¸μ·´Ò¥ ±¨´ §Ò, ±μÉμ·Ò¥ Ëμ¸Ëμ·¨²¨·ÊÕÉ ³¥¤¨ Éμ·Ò, ¢ ¸¢μÕ μÎ¥·¥¤Ó ¶·¨¢²¥± ÕШ¥ ÔËË¥±Éμ·´Ò¥ ±¨´ §Ò [5]. ËË¥±Éμ·´Ò¥ ±¨´ §Ò ±É¨¢¨·ÊÕÉ¸Ö ¢
·¥§Ê²ÓÉ É¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ¸¥´¸μ·´Ò³¨ ±¨´ § ³¨. ˆ, ´ ±μ´¥Í, ±É¨¢¨·μ¢ ´´Ò¥ ÔËË¥±Éμ·´Ò¥ ±¨´ §Ò Ëμ¸Ëμ·¨²¨·ÊÕÉ ¸¶¥Í¨Ë¨Î¥¸±¨¥ ³¨Ï¥´´Ò¥
¡¥²±¨ (ÔËË¥±Éμ·Ò), μ¸ÊÐ¥¸É¢²ÖÕШ¥ μ¸É ´μ¢±Ê ±²¥Éμδμ£μ ¤¥²¥´¨Ö. ƒ¥´¥·¨·Ê¥³Ò° ¸¨£´ ² Î¥±¶μ°´É μ£· ´¨Î¨¢ ¥É¸Ö Ö¤·μ³ ¨ ´¥ ¢ÒÌμ¤¨É § ¥£μ ¶·¥¤¥²Ò ¢ ͨÉ춲 §³Ê [6]. μ± § ´μ, ÎÉμ ¥¤¨´¨Î´Ò° ¤¢Ê´¨É¥¢μ° · §·Ò¢ („),
¨´¤Êͨ·μ¢ ´´Ò° -Ô´¤μ´Ê±²¥ §μ° ¢ μ¤´μ³ ¨§ Ö¤¥· ¤¢ÊÖ¤¥·´μ£μ £¥É¥·μ± ·¨μ´ , ¢Ò§Ò¢ ² μ¸É ´μ¢±Ê ¤¥²¥´¨Ö Ö¤· ¢ ´ Ë §¥. ·¨ ÔÉμ³ Ê ¢Éμ·μ£μ ´¥¶μ¢·¥¦¤¥´´μ£μ Ö¤· ´ ¡²Õ¤ ²¨ ´μ·³ ²Ó´μ¥ ¤¥²¥´¨¥, ¨ ¶·μ¨¸Ì줨² ¢ÒÌμ¤
¨§ ³¨Éμ§ .
–¨±²¨´-§ ¢¨¸¨³ Ö ±¨´ § CDK1/CDC28 Ö¢²Ö¥É¸Ö ¶·¨¢²¥± É¥²Ó´μ° ³¨Ï¥´ÓÕ ¤²Ö Î¥±¶μ°´Éμ¢, ¶μ¸±μ²Ó±Ê ÊÎ ¸É¢Ê¥É ¢ ·¥£Ê²Öͨ¨ ¶·μÌ즤¥´¨Ö ±²¥Éμδμ£μ ͨ±² [7]. ¤´ ±μ ¢ μɲ¨Î¨¥ μÉ ¡μ²ÓϨ´¸É¢ Ôʱ ·¨μɨΥ¸±¨Ì μ·£ ´¨§³μ¢ Ê ¶μαÊÕÐ¨Ì¸Ö ¤·μ¦¦¥° ¶μ²´ Ö ¨´ ±É¨¢ ꬅ ±¨´ §Ò ´¥¢μ§³μ¦´ ,
É ± ± ± ÔÉμ ¥¤¨´¸É¢¥´´ Ö Í¥´É· ²Ó´ Ö ±¨´ § , ·¥£Ê²¨·ÊÕÐ Ö ³´μ£μΨ¸²¥´´Ò¥ ¶·μÍ¥¸¸Ò ±²¥Éμδμ£μ ¤¥²¥´¨Ö. Œμ²¥±Ê²Ö·´Ò¥ ³¥Ì ´¨§³Ò ·¥£Ê²Öͨ¨
μ¸É ´μ¢±¨ ±²¥Éμδμ£μ ͨ±² ±¨´ §μ° CDK1 ¶·¨ ¶μ¢·¥¦¤¥´¨¨ ±μ³¶μ´¥´Éμ¢
±²¥É±¨ ¢ ´ ¸ÉμÖÐ¥¥ ¢·¥³Ö ¨§ÊÎ¥´Ò ´¥¤μ¸É Éμδμ. ‚ ¤ ´´μ° ¸É ÉÓ¥ · ¸¸³μÉ·¥´Ò ´¥±μÉμ·Ò¥ ¸¶¥±ÉÒ ÊÎ ¸É¨Ö ±¨´ §Ò CDK1 ¢ Î¥±¶μ°´É Ì, μ¸μ¡μ¥ ¢´¨³ ´¨¥ μ¡· Ð ¥É¸Ö ´ · §²¨Î¨Ö ³¥Ì ´¨§³μ¢ Î¥±¶μ°´É ¢ · §´ÒÌ Ë § Ì ±²¥Éμδμ£μ ͨ±² .
1
2
3
CDK1 ·¥£Ê²¨·Ê¥É ±É¨¢´μ¸ÉÓ ³´μ£μΨ¸²¥´´ÒÌ ¡¥²±μ¢ Î¥±¶μ°´É ¶μ¢·¥¦¤¥´¨° „Š (¸Ê¡¸É· ÉÒ CDK1 ¢Ò¤¥²¥´Ò
· ³±μ°). ‘¥´¸μ·Ò ÎÊ¢¸É¢ÊÕÉ ¶μ¢·¥¦¤¥´¨Ö „Š ¨²¨ ·¥¶²¨± ɨ¢´Ò° ¸É·¥¸¸ ¨ ±É¨¢¨·ÊÕÉ PIKKs ±¨´ §Ò Mec1 ¨ Tel1.
±É¨¢ ꬅ ÔËË¥±Éμ·´ÒÌ ±¨´ § (Rad53, Dun1 ¨ Chk1) μ¶μ¸·¥¤Ê¥É¸Ö ¤¢Ê³Ö ³¥¤¨ Éμ· ³¨ Å Rad9 ¨ Œrc1. …¸²¨ Mrc1
ËÊ´±Í¨μ´¨·Ê¥É ¢ ± Î¥¸É¢¥ ³¥¤¨ Éμ· ¢ ¶·μÍ¥¸¸¥ ·¥¶²¨± ͨ¨ „Š, Éμ Rad9 ³μ¦¥É ʧ´ ¢ ÉÓ ¶μ¢·¥¦¤¥´¨Ö, ±μÉμ·Ò¥
¢μ§´¨± ÕÉ ¢´¥ S-Ë §Ò. Œ¥¤¨ Éμ· Rad9 (¨²¨ Mrc1) Ëμ¸Ëμ·¨²¨·Ê¥É¸Ö ±¨´ §μ° Œ¥¸1 ¢ μÉ¢¥É ´ ¶μ¢·¥¦¤¥´¨Ö „Š.
Éμ μ¡¥¸¶¥Î¨¢ ¥É ¥£μ ¸¸μͨ Í¨Õ ¸ ±¨´ §μ° Rad53, ¶·¨¢μ¤ÖÐÊÕ ± ±É¨¢ ͨ¨ Rad53 ±¨´ §μ° Œ¥¸1 ¨ ¶μ¸²¥¤ÊÕÐ¥³Ê ¢ÉμËμ¸Ëμ·¨²¨·μ¢ ´¨Õ Rad53. ËË¥±Éμ·´Ò¥ ¶·μÉ¥¨´±¨´ §Ò Ëμ¸Ëμ·¨²¨·ÊÕÉ ¨ ±É¨¢¨·ÊÕÉ ³´μ£μΨ¸²¥´´Ò¥
³¨Ï¥´¨ (Éμ²Ó±μ Î ¸ÉÓ ÔÉ¨Ì ¡¥²±μ¢ ʱ § ´ ´ ·¨¸Ê´±¥), μ¸ÊÐ¥¸É¢²ÖÕШ¥ μ¸É ´μ¢±Ê ±²¥Éμδμ£μ ͨ±² ¨ ¨¸¶· ¢²¥´¨¥ ´ ·ÊÏ¥´¨Ö. ‚ ¸²ÊÎ ¥ ·¥£Ê²Öͨ¨ É· ´¸±·¨¶Í¨¨ ÔËË¥±Éμ· ³¨ ¸²Ê¦ É É· ´¸±·¨¶Í¨μ´´Ò¥ Ë ±Éμ·Ò, ʧ´ ÕШ¥
cis-Ô²¥³¥´ÉÒ ¢ ¶·μ³μÉμ·´μ° μ¡² ¸É¨ ¨´¤Êͨ¡¥²Ó´ÒÌ £¥´μ¢. ¥±μÉμ·Ò¥ ¨§ ÔÉ¨Ì ÔËË¥±Éμ·μ¢ É ±¦¥ Ëμ¸Ëμ·¨²¨·ÊÕɸÖ
±¨´ §μ° CDK1, ÌμÉÖ ¶μ¸²¥¤¸É¢¨Ö μ¤´μ¢·¥³¥´´μ£μ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ¤¢Ê³Ö ±¨´ § ³¨ ´¥ ¢¸¥£¤ ¶μ´ÖÉ´Ò. ¶·¨³¥·,
CDK1 ³μ¦¥É Ëμ¸Ëμ·¨²¨·μ¢ ÉÓ Rad9, ʸ¨²¨¢ Ö ¸¨£´ ²Ó´Ò° ± ¸± ¤, ¨²¨ Rad53, Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ±μÉμ·μ° ¨³¥¥É
§´ Î¥´¨¥ ´¥ ¢ ±É¨¢ ͨ¨, ¢ ¶·¥¤μÉ¢· Ð¥´¨¨ ¤ ¶É ͨ¨.
‘Ì¥³ Î¥±¶μ°´Éμ¢, ¨´¤Êͨ·Ê¥³ÒÌ ·¥¶²¨± ɨ¢´Ò³ ¸É·¥¸¸μ³ ¨ ¶μ¢·¥¦¤¥´¨Ö³¨ „Š
™Ÿ ‘•…Œ —…Š‰’
“ Saccharomyces cerevisiae ´ ¨¡μ²¥¥ Ìμ·μÏμ ¨§ÊÎ¥´Ò Î¥±¶μ°´ÉÒ Í¥²μ¸É´μ¸É¨ „Š, ¨²¨ Î¥±¶μ°´ÉÒ, ¨´¤Êͨ·Ê¥³Ò¥ ¶μ¢·¥¦¤¥´¨Ö³¨ „Š. ‘¨£´ ²μ³ ¤²Ö ±É¨¢ ͨ¨ Î¥±¶μ°´É ¸²Ê¦¨É μ¤´μ´¨É¥¢ Ö „Š (μ´„Š) [8, 9].
¥·¢¨Î´Ò¥ ¶μ¢·¥¦¤¥´¨Ö „Š, ¶·μÍ¥¸¸¨´£ ±μÉμ·ÒÌ ¶·¨¢μ¤¨É ± μ¡· §μ¢ ´¨Õ ÊÎ ¸É± μ´„Š, É ±¦¥ ±É¨¢¨·ÊÕÉ Î¥±¶μ°´É (¸³. ·¨¸Ê´μ±). ’ ±, ±É¨¢ Í¨Ö Î¥±¶μ°´É ¶μ¢·¥¦¤¥´¨Ö³¨, ¨´¤Êͨ·μ¢ ´´Ò³¨ “”-¸¢¥Éμ³, μ¡Ê¸²μ¢²¥´ ¶·μÍ¥¸¸¨´£μ³ ¶μ¢·¥¦¤¥´¨° ¢μ ¢·¥³Ö Ô±¸Í¨§¨μ´´μ° ·¥¶ · ͨ¨ NER
(nucleotide excision repair). ¥²μ± Ô±¸Í¨§¨μ´´μ° ·¥¶ · ͨ¨ Rad14, ±μÉμ·Ò° ʧ´ ¥É ¨ ¸¢Ö§Ò¢ ¥É¸Ö ¸ ¶μ¢·¥¦¤¥´¨¥³ „Š, ˨§¨Î¥¸±¨ ¢§ ¨³μ¤¥°¸É¢Ê¥É
¸ ¸¥´¸μ·μ³ Î¥±¶μ°´É Ddc1 [10]. ·μÉμ³¥· Rad14 ¢Ìμ¤¨É ¢ ¸μ¸É ¢ Ë ±Éμ· NEF1 (Rad14-Rad1-Rad10) ¨ μ¶μ¸·¥¤Ê¥É ¤μ¸É ¢±Ê ± ¶μ¢·¥¦¤¥´¨Õ Ô´¤μ´Ê±²¥ §Ò Rad1-Rad10, μ¡· §ÊÕÐ¥° ´¨± ¸ 5 -±μ´Í μÉ ¶μ¢·¥¦¤¥´¨Ö. ±É¨¢ Í¨Ö Î¥±¶μ°´É „ „Š ¶·μ¨¸Ìμ¤¨É ¢ ·¥§Ê²ÓÉ É¥ ¶·μÍ¥¸¸¨´£ „ Ô±§μ´Ê±²¥ §´Ò³ ±μ³¶²¥±¸μ³ MRX (Mre11-Rad50-Xrs2)-Sae2, · ¸Ð¥¶²ÖÕШ³ 5 -´¨ÉÓ
¸ μ¡· §μ¢ ´¨¥³ ±μ·μɱμ£μ (∼ 100 ´Ê±²¥μɨ¤μ¢) 3 -±μ´Í μ´„Š [11, 12]. ˆ´¤Ê±Í¨Ö Î¥±¶μ°´É ¶·μ¨¸Ìμ¤¨É É ±¦¥ ¶·¨ ´ ±μ¶²¥´¨¨ μ´„Š ¢ É¥²μ³¥· Ì Ê
³ÊÉ ´É cdc13-1 ¨ ´ ±μ¶²¥´¨¨ „ ¶·¨ ¨´ ±É¨¢ ͨ¨ „Š-²¨£ §Ò Cdc9.
G1/S- ¨ G2/M-Î¥±¶μ°´ÉÒ. ‘¥´¸μ·Ò, ʧ´ ÕШ¥ ¶μ¢·¥¦¤¥´¨Ö, ¢Ò§¢ ´´Ò¥ “”-¸¢¥Éμ³, ¨μ´¨§¨·ÊÕÐ¥° · ¤¨ ͨ¥° (ˆ) ¨ „ Ô´¤μ£¥´´μ£μ ¶·μ¨¸Ì즤¥´¨Ö, ¨´¤Êͨ·ÊÕÉ G1/S- ¨ G2/M-Î¥±¶μ°´ÉÒ. “Î ¸É±¨ μ´„Š ʧ´ ÕɸÖ
´¥¸±μ²Ó±¨³¨ ¡¥²±μ¢Ò³¨ ±μ³¶²¥±¸ ³¨ (¸³. ·¨¸Ê´μ±), É ±¨³¨ ± ± RPA (replication protein A), Rad24-RFC ¨ Ddc1-Mec3-Rad17 [13]. ·¥¦¤¥ ¢¸¥£μ, ÊÎ ¸É±¨
μ´„Š ¶μ±·Ò¢ ÕÉ¸Ö £¥É¥·μÉ·¨³¥·μ³ RPA (Rpa1-Rpa2-Rpa3). Š £· ´¨Í¥
³¥¦¤Ê RPA-μ´„Š ¨ ¤Ê¶²¥±¸μ³ „Š ¤μ¸É ¢²Ö¥É¸Ö £¥É¥·μÉ·¨³¥· Ddc1-Mec3Rad17 [14] (Ê Î¥²μ¢¥± μ·Éμ²μ£¨ hRad9, hHus1, hRad1), ¶·μÖ¢²ÖÕШ° ¸Ìμ¤¸É¢μ ¸μ ¸±·¥¶±μ° ¨²¨ ·¥¶²¨± ɨ¢´Ò³ Ë ±Éμ·μ³ ¶·μÍ¥¸¸¨¢´μ¸É¨ £μ³μÉ·¨³¥·μ³ PCNA (Pol30). ‚ ¶·μÍ¥¸¸¥ ·¥¶²¨± ͨ¨ § £·Ê§± ¸±·¥¶±¨ PCNA ´ £· ´¨ÍÊ 3 -μ´„Š/¤´„Š μ¸ÊÐ¥¸É¢²Ö¥É¸Ö £¥É¥·μ¶¥´É ³¥·´Ò³ ±μ³¶²¥±¸μ³ RFC
(replication factor C). ‚ ¸ °É¥ ¶μ¢·¥¦¤¥´¨Ö „Š ±μ³¶²¥±¸ Ddc1-Mec3-Rad17
§ £·Ê¦ ¥É¸Ö ´ £· ´¨ÍÊ 5 -μ´„Š/¤´„Š ³μ¤¨Ë¨Í¨·μ¢ ´´μ° Ëμ·³μ° RFC,
¢ ±μÉμ·μ° ¸Ê¡Ñ¥¤¨´¨Í Rfc1 § ³¥´¥´ Î¥±¶μ°´É-¸¶¥Í¨Ë¨Î´μ° ¸Ê¡Ñ¥¤¨´¨Í¥°
Rad24 (Rad24-RFC).
‚ ¶¥·¥¤ Î¥ ¸¨£´ ² ¡μ²ÓÏμ¥ §´ Î¥´¨¥ ¨³¥ÕÉ ¶·μÉ¥¨´±¨´ §Ò. ‘¥´¸μ·´Ò¥
¨ ÔËË¥±Éμ·´Ò¥ ±¨´ §Ò ±μ´¸¥·¢ ɨ¢´Ò Ê Ôʱ ·¨μÉ ¨ Ìμ·μÏμ μÌ · ±É¥·¨§μ¢ ´Ò. Š ¸¥´¸μ·´Ò³ ±¨´ § ³, ¸¢Ö§Ò¢ ÕШ³¸Ö ¸ ¶μ¢·¥¦¤¥´¨Ö³¨ „Š, μÉ´μ¸ÖÉ¸Ö ±¨´ §Ò Œ¥¸1 ¨ Tel1, μ·Éμ²μ£¨ PIKK (phosphoinositide 3 kinase-related
kinases) ±¨´ § Ê ³²¥±μ¶¨É ÕÐ¨Ì Å ATR ¨ ATM ¸μμÉ¢¥É¸É¢¥´´μ. Š¨´ §Ò
Mec1 ¨ Tel1 ¶·¨¢²¥± ÕÉ¸Ö ± ¶μ¢·¥¦¤¥´¨Õ „Š ¸ ¶μ³μÐÓÕ Ddc2 ¨ MRX
¸μμÉ¢¥É¸É¢¥´´μ. “ ¤·μ¦¦¥° Œ¥¸1 Ö¢²Ö¥É¸Ö μ¸´μ¢´μ° ¸¨£´ ²Ó´μ° ³μ²¥±Ê²μ°
Î¥±¶μ°´Éμ¢. Š ÔËË¥±Éμ·´Ò³ ±¨´ § ³ μÉ´μ¸ÖÉ¸Ö Rad53 (Ê Î¥²μ¢¥± hChk2),
Dun1 ¨ Chk1 (hChk1).
4
‘¨£´ ²Ó´ Ö ±¨´ § Œ¥¸1 ¸¸μͨ¨·Ê¥É ¸ ¶μ¢·¥¦¤¥´´Ò³ Ì·μ³ É¨´μ³ ¶μ¸·¥¤¸É¢μ³ ¡¥²± Ddc2, ±μÉμ·Ò° ¢§ ¨³μ¤¥°¸É¢Ê¥É ± ± ¸ „Š, É ± ¨ ¸ RPAμ´„Š [15, 16]. ‘¢Ö§Ò¢ ´¨¥ Mec1-Ddc2 ¸ RPA ¶·¨¢μ¤¨É ± ±É¨¢ ͨ¨ ±¨´ §Ò,
¶·¨ ÔÉμ³ ¤¢¥ ¸Ê¡Ñ¥¤¨´¨ÍÒ Œ¥¸1 Ëμ¸Ëμ·¨²¨·ÊÕÉ ¤·Ê£ ¤·Ê£ , ¨ ±μ³¶²¥±¸ · §·ÊÏ ¥É¸Ö, ¢Ò¸¢μ¡μ¦¤ Ö ±É¨¢´ÊÕ Ëμ·³Ê ±¨´ §Ò Œ¥¸1, ±μÉμ· Ö ¢§ ¨³μ¤¥°¸É¢Ê¥É ¸ ¸Ê¡¸É· É ³¨ [17, 18]. ɳ¥É¨³, ÎÉμ ±μ³¶²¥±¸ Rad24-RFC ´¥μ¡Ì줨³
Éμ²Ó±μ ¤²Ö § £·Ê§±¨ Ddc1-Mec3-Rad17 ¨ ´¥ ´Ê¦¥´ ¤²Ö ±É¨¢ ͨ¨ Î¥±¶μ°´É ,
¥¸²¨ ±μ³¶²¥±¸ c Mec1-Ddc2 ʦ¥ μ¡· §μ¢ ²¸Ö. ‘ °É ¶μ¢·¥¦¤¥´¨Ö „Š, ¶μ¢¨¤¨³μ³Ê, ¸²Ê¦¨É ¶² ÉËμ·³μ° ¤²Ö ±μ´Í¥´É· ͨ¨ ¤ ¶Éμ·´ÒÌ ³μ²¥±Ê². ·μÉμ³¥· Ddc1 ±μ³¶²¥±¸ Ddc1-Mec3-Rad17 Ê¢¥²¨Î¨¢ ¥É ±¨´ §´ÊÕ ±É¨¢´μ¸ÉÓ
Œ¥¸1, ± ± ´ ¶·Ö³ÊÕ, É ± ¨ ·¥±·Êɨ·ÊÖ ¢Éμ·μ° ±É¨¢ Éμ· Œ¥¸1 Å ¡¥²μ±
Dpb11 [19Ä21].
¤´ ±μ ¤²Ö ¶μ¸²¥¤ÊÕÐ¥° ±É¨¢ ͨ¨ ÔËË¥±Éμ·´μ° ±¨´ §Ò Rad53 ´¥¤μ¸É ÉμÎ´μ ±μ²μ± ²¨§ ͨ¨ ±μ³¶²¥±¸μ¢ Œ¥¸1-Ddc2 ¨ Ddc1-Mec3-Rad17, ¤μ¶μ²´¨É¥²Ó´μ ´¥μ¡Ì줨³ ³¥¤¨ Éμ· Rad9. „μ¸É ¢±Ê Rad9 μ¸ÊÐ¥¸É¢²Ö¥É ±μ³¶²¥±¸
(Ddc1-Mec3-Rad17)-Dpb11 [22, 23]. Š·μ³¥ Éμ£μ, ¤²Ö ÔËË¥±É¨¢´μ° ¤μ¸É ¢±¨
Rad9 ¨ μ·Éμ²μ£ Ê Î¥²μ¢¥± 53BP1 ´¥μ¡Ì줨³Ò, ¶μ ±· °´¥° ³¥·¥, ¤¢¥ ³μ¤¨Ë¨± ͨ¨ £¨¸Éμ´μ¢ Å Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ 2 ¨ ³¥É¨²¨·μ¢ ´¨¥ 3(4) [24, 25].
‚ μÉ¢¥É ´ ¶μ¢·¥¦¤¥´¨¥ „Š ±É¨¢´Ò¥ ±¨´ §Ò Œ¥¸1 ¨²¨ Tel1 ¡Ò¸É·μ Ëμ¸Ëμ·¨²¨·ÊÕÉ ¤¢¥ ¸Ê¡Ñ¥¤¨´¨ÍÒ RPA (Rpa1 ¨ Rpa2) ¨ ‘-±μ´ÍÒ £¨¸Éμ´μ¢ 2 ¢μ±·Ê£ „ [26, 27]. ƒ¨¸Éμ´ 2 Ëμ¸Ëμ·¨²¨·Ê¥É¸Ö ¶μ ¸¥·¨´Ê 129 (2S129ph)
´ · ¸¸ÉμÖ´¨¨ 50 É. ¶. ´. ¶μ μ¡¥ ¸Éμ·μ´Ò μÉ ¶μ¢·¥¦¤¥´¨Ö [28]. É ³μ¤¨Ë¨± Í¨Ö μ¡¥¸¶¥Î¨¢ ¥É ¢§ ¨³μ¤¥°¸É¢¨¥ ¸ Rad9. ´ ²μ£¨Î´μ Ê ¶μ§¢μ´μδÒÌ 53‚1
¸¸μͨ¨·Ê¥É ¸ ¢ ·¨ ´Éμ³ £¨¸Éμ´ 2 (2•S139ph) ¶μ¸²¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö £¨¸Éμ´ ±¨´ § ³¨ ATM ¨²¨ ATR [29, 30]. Š·μ³¥ Éμ£μ, ±μ´¸É¨ÉÊɨ¢´μ¥
³¥É¨²¨·μ¢ ´¨¥ ²¨§¨´ 79 £¨¸Éμ´ 3 (3Š79me) ³¥É¨²É· ´¸Ë¥· §μ° Dot1
μ¶μ¸·¥¤Ê¥É ¢§ ¨³μ¤¥°¸É¢¨¥ c Tudor-¤μ³¥´μ³ Rad9 [24, 31]. ’ ± ± ± ¢ μÉ¢¥É ´ ¶μ¢·¥¦¤¥´¨¥ „Š ³¥É¨²¨·μ¢ ´¨¥ £¨¸Éμ´ 3 ´¥ ¨§³¥´Ö¥É¸Ö, ¶·¥¤¶μ² £ ¥É¸Ö,
ÎÉμ ¸¢Ö§Ò¢ ´¨¥ ¡¥²±μ¢ Î¥±¶μ°´É ¸ ³μ¤¨Ë¨Í¨·μ¢ ´´Ò³ £¨¸Éμ´μ³ ¸É ´μ¢¨É¸Ö
¢μ§³μ¦´Ò³ ¢ ·¥§Ê²ÓÉ É¥ ¨§³¥´¥´¨Ö ¸É·Ê±ÉÊ·Ò Ì·μ³ É¨´ , ¶·μ¨¸Ìμ¤ÖÐ¥£μ ¢
μÉ¢¥É ´ ¢μ§´¨±´μ¢¥´¨¥ „ [24]. ´ ²μ£¨Î´μ ³¥É¨²¨·μ¢ ´¨¥ ²¨§¨´ 20 £¨¸Éμ´ 4 (4Š20me) ´¥μ¡Ì줨³μ ¤²Ö ¶μ¤¤¥·¦ ´¨Ö 53‚1 [32]. ·¨ ´ ²¨Î¨¨
¤¢ÊÌ ³¥Éμ± ¡¥²μ± Rad9 ¸¢Ö§Ò¢ ¥É¸Ö ¸ Ì·μ³ É¨´μ³ [33] ¨ ±É¨¢´μ ¶·¨¢²¥± ¥É
¢¸¶μ³μ£ É¥²Ó´Ò¥ ¡¥²±¨ ± „. ’ ±¨³ μ¡· §μ³, ¤ ¶Éμ·´Ò¥ ¡¥²±¨ Ê ¤·μ¦¦¥°
¨ ¶μ§¢μ´μδÒÌ ¤²Ö ¶μ¸ ¤±¨ ´ Ì·μ³ É¨´ ¢¡²¨§¨ ¸ °É ¶μ¢·¥¦¤¥´¨Ö ¨¸¶μ²Ó§ÊÕÉ ¸Ì즨¥ ³¥Ì ´¨§³Ò Å Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ¨ ³¥É¨²¨·μ¢ ´¨¥ ±μ·μ¢ÒÌ £¨¸Éμ´μ¢. ²¨³¨´ Í¨Ö μ¡¥¨Ì ³μ¤¨Ë¨± ͨ° (Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ 2S129ph ¨
³¥É¨²¨·μ¢ ´¨¥ 3Š79me) ¸´¨¦ ¥É Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ¶μ¸²¥ μ¡²ÊÎ¥´¨Ö ±²¥Éμ± ˆ [25]. μ-¢¨¤¨³μ³Ê, „Š ¢Ò¸Éʶ ¥É ´¥ Éμ²Ó±μ ¢ ± Î¥¸É¢¥ ¶² ÉËμ·³Ò
¤²Ö ¸¡μ·±¨ ¤ ¶Éμ·´ÒÌ ³μ²¥±Ê² ¢¡²¨§¨ ¸¥´¸μ·´ÒÌ ±¨´ §, ´μ É ±¦¥ ÊÎ ¸É¢Ê¥É
¢ Ëμ·³¨·μ¢ ´¨¨ ¸É·Ê±ÉÊ·Ò Ì·μ³ É¨´ ¢¡²¨§¨ ¶μ¢·¥¦¤¥´¨Ö, ±μÉμ· Ö μ¡¥¸¶¥Î¨¢ ¥É ʸ¨²¥´¨¥ ¸¨£´ ² , ʤ¥·¦¨¢ Ö ±μ³¶μ´¥´ÉÒ Î¥±¶μ°´É .
5
‚ ¤ ²Ó´¥°Ï¥³ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ³¥¤¨ Éμ· Rad9 ¸¥´¸μ·´μ° ±¨´ §μ°
Œ¥¸1 μ¡¥¸¶¥Î¨¢ ¥É ±É¨¢ Í¨Õ ¨ 첨£μ³¥·¨§ Í¨Õ Rad9. ˆ´¤Êͨ·μ¢ ´´μ¥ ¶μ¢·¥¦¤¥´¨Ö³¨ „Š Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ Rad9 ±μ··¥²¨·Ê¥É ¸ ·¥³μ¤¥²¨·μ¢ ´¨¥³
Rad9-±μ³¶²¥±¸ (∼ 850 ±„ ) ¢ ³¥´ÓϨ° ¶μ · §³¥·Ê ±μ³¶²¥±¸ (560 ±„ ), ¸μ¤¥·¦ Ш° ¨´¤Êͨ·μ¢ ´´ÊÕ ¶μ¢·¥¦¤¥´¨Ö³¨ „Š £¨¶¥·Ëμ¸Ëμ·¨²¨·μ¢ ´´ÊÕ
Ëμ·³Ê Rad9 [34, 35]. É Ëμ·³ ¶μ§¢μ²Ö¥É Rad9 μ¸ÊÐ¥¸É¢²ÖÉÓ ËÊ´±Í¨Õ
¤ ¶Éμ· ± É ²¨§ ¤²Ö ±É¨¢ ͨ¨ ±¨´ §Ò Rad53 [36]. Rad53 ¸¢Ö§Ò¢ ¥É¸Ö
¸ Ëμ¸Ëμ·¨²¨·μ¢ ´´Ò³ Rad9 Î¥·¥§ ¤μ³¥´Ò FHA (forkhead homology associated), μÉ¢¥É¸É¢¥´´Ò¥ § ¢§ ¨³μ¤¥°¸É¢¨¥ ³¥¦¤Ê Ëμ¸Ëμ·¨²¨·μ¢ ´´Ò³¨ ¡¥²± ³¨ [37, 38]. Éμ ¸¢Ö§Ò¢ ´¨¥ ¶μ¤£μÉ ¢²¨¢ ¥É Rad53 ± Ëμ¸Ëμ·¨²¨·μ¢ ´¨Õ
±¨´ §μ° Œ¥¸1 [39]. „²Ö ¶μ²´μ° ±É¨¢ ͨ¨ Rad53 ´¥μ¡Ì줨³μ ¤μ¶μ²´¨É¥²Ó´μ¥ ¢ÉμËμ¸Ëμ·¨²¨·μ¢ ´¨¥ [35, 40], ±μÉμ·μ¥ ± É ²¨§¨·Ê¥É¸Ö ¶μ¢ÒÏ¥´¨¥³ ²μ± ²Ó´μ° ±μ´Í¥´É· ͨ¨ Rad53 ´ Rad9-¶² ÉËμ·³¥ [36].
‚¸¥£μ ¢Ò¤¥²¥´μ 13 ¸ °Éμ¢ ¢ÉμËμ¸Ëμ·¨²¨·μ¢ ´¨Ö Rad53 ¨ 14 ¸ °Éμ¢
Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ¤·Ê£¨³¨ ±¨´ § ³¨, ¢ Éμ³ Î¨¸²¥ Mec1 ¨ CDK1 (¸³. ´¨¦¥).
Œ´μ¦¥¸É¢¥´´μ¸ÉÓ ¸ °Éμ¢ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö μ¡¥¸¶¥Î¨¢ ¥É ³¥Ì ´¨§³ ¶¥·¥±²ÕÎ¥´¨Ö, ¨¸¶μ²Ó§ÊÕШ° ±·¨É¨Î¥¸±¨° Ê·μ¢¥´Ó Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ¤²Ö ¶μ²´μ° ±É¨¢ ͨ¨. —¥ÉÒ·¥ ±Í¥¶Éμ·´ÒÌ ¸ °É · ¸¶μ² £ ÕÉ¸Ö ¢ SQ/TQ-±² ¸É¥· Ì
¢¡²¨§¨ ± ¦¤μ£μ ¨§ ¤¢ÊÌ ¤μ³¥´μ¢ FHA. ‘-±μ´Í¥¢μ° FHA2-¤μ³¥´ μ¡¥¸¶¥Î¨¢ ¥É
¢§ ¨³μ¤¥°¸É¢¨¥ ¸ Ëμ¸Ëμ·¨²¨·μ¢ ´´Ò³ ³¥¤¨ Éμ·μ³ Rad9 ¨ Ö¢²Ö¥É¸Ö ±·¨É¨Î´Ò³ ¤²Ö ¶·¨¥³ ¸¨£´ ² Î¥±¶μ°´É , ±É¨¢¨·μ¢ ´´μ£μ ¶μ¢·¥¦¤¥´¨Ö³¨ „Š.
N-±μ´Í¥¢μ° FHA1-¤μ³¥´ ¢§ ¨³μ¤¥°¸É¢Ê¥É ´¥ Éμ²Ó±μ ¸ Rad9, ´μ ¨ ¸ ±μ³¶μ´¥´Éμ³ ·¥¶²¨± ɨ¢´μ£μ Î¥±¶μ°´É £¥²¨± §μ° Sgs1. ‚¸¥£μ ¢Ò¤¥²¥´μ 26 ¡¥²±μ¢,
¢§ ¨³μ¤¥°¸É¢ÊÕÐ¨Ì ¸ FHA1 ¨ μÉ¢¥É¸É¢¥´´ÒÌ § Ϩ·μ±¨° ¸¶¥±É· ËÊ´±Í¨°
Rad53 [41], ¢ Éμ³ Î¨¸²¥ ¸ Ëμ¸Ë É § ³¨ Ptc2 ¨ Ptc3, ÊÎ ¸É¢ÊÕШ³¨ ¢ ¨´£¨¡¨·μ¢ ´¨¨ ËÊ´±Í¨μ´¨·μ¢ ´¨Ö Rad53 [42].
±É¨¢¨·μ¢ ´´Ò° Rad53 ¶μ±¨¤ ¥É ¸ °É ¶μ¢·¥¦¤¥´¨Ö ¨ Ëμ¸Ëμ·¨²¨·Ê¥É
ÔËË¥±Éμ·Ò Î¥±¶μ°´É , ÎÉμ ¢¥¤¥É ± μ¸É ´μ¢±¥ ±²¥Éμδμ£μ ͨ±² ¨ ·¥£Ê²Öͨ¨ É· ´¸±·¨¶Í¨¨ (¸³. ·¨¸Ê´μ±). Š ¨¤¥´É¨Ë¨Í¨·μ¢ ´´Ò³ ³¨Ï¥´Ö³ Rad53
μÉ´μ¸ÖÉ¸Ö É· ´¸±·¨¶Í¨μ´´Ò° ·¥£Ê²ÖÉμ· Swi6 ¨ ±¨´ §Ò Dun1 ¨ Dbf4. ”μ¸Ëμ·¨²¨·μ¢ ´¨¥ ÔÉ¨Ì ³¨Ï¥´¥° ¢¥¤¥É ± ¶μ¤ ¢²¥´¨Õ G1-ͨ±²¨´μ¢, · §·ÊÏ¥´¨Õ ¨´£¨¡¨Éμ· ·¨¡μ´Ê±²¥μɨ¤·¥¤Ê±É §Ò Sml1 ¨ ¨´£¨¡¨·μ¢ ´¨Õ μɱ·ÒɨÖ
¶μ§¤´¨Ì ¸ °Éμ¢ ·¥¶²¨± ͨ¨ ori ¸μμÉ¢¥É¸É¢¥´´μ. Rad53 ÊÎ ¸É¢Ê¥É ¢ ¸É ¡¨²¨§ ͨ¨ ·¥¶²¨± ɨ¢´μ° ¢¨²±¨, ·¥£Ê²Öͨ¨ É· ´¸±·¨¶Í¨¨ ¨ Ê·μ¢´Ö ´ ±μ¶²¥´¨Ö
£¨¸Éμ´μ¢ [43].
μ²ÓÏ Ö Î ¸ÉÓ Rad53-§ ¢¨¸¨³μ£μ μÉ¢¥É Ê ¤·μ¦¦¥° μ¶·¥¤¥²Ö¥É¸Ö ±¨´ §μ° Mec1 [44, 45]. ‘¥´¸μ·´ Ö ±¨´ § Tel1 ¶μÌμ¦ ´ Œ¥¸1 ¨ ³μ¦¥É μ¸ÊÐ¥¸É¢²ÖÉÓ ´¥±μÉμ·Ò¥ ¨§ ¥¥ ËÊ´±Í¨°. Tel1 Ëμ¸Ëμ·¨²¨·Ê¥É ¨ ±É¨¢¨·Ê¥É Rad53,
¨¸¶μ²Ó§ÊÖ ³¥¤¨ Éμ· Rad9, μ¤´ ±μ ¤²Ö ÔÉμ£μ ´¥ É·¥¡ÊÕÉ¸Ö ¡¥²±¨ Ddc1 ¨
Dpb11 [46, 47]. Tel1 ¢´μ¸¨É ¸² ¡Ò° ¢±² ¤ ¢ ±É¨¢ Í¨Õ Rad53, ¨ ÔÉμ ¶·μ¨¸Ìμ¤¨É ¢ ¸¶¥Í¨Ë¨Î¥¸±¨Ì ʸ²μ¢¨ÖÌ ¶μ¢·¥¦¤¥´¨Ö „Š [48Ä50]. —¥±¶μ°´É
¶μ¢·¥¦¤¥´¨° „Š ¨³¥¥É, ¶μ ±· °´¥° ³¥·¥, ¤¢ ¶Êɨ, ±μ´É·μ²¨·Ê¥³Ò¥ ÔËË¥±6
Éμ·´Ò³¨ ±¨´ § ³¨ Rad53 ¨ Chk1. ”μ¸Ëμ·¨²¨·μ¢ ´¨¥ Chk1 É ±¦¥ § ¢¨¸¨É
μÉ Rad9 [51Ä53].
Intra S-Î¥±¶μ°´É. ˆ´ Ö ¸¨ÉÊ Í¨Ö ¸±² ¤Ò¢ ¥É¸Ö ¶·¨ ·¥¶²¨± ͨ¨ „Š.
‚ ¶·μÍ¥¸¸¥ ¸¨´É¥§ „Š ·¥¶²¨± ɨ¢´ Ö ¢¨²± ¶μ¤¢¥·£ ¥É¸Ö · §²¨Î´Ò³ ¢¨¤ ³
¸É·¥¸¸ . Œ´μ£¨¥ ¢´¥Ï´¨¥ Ë ±Éμ·Ò ¢Ò§Ò¢ ÕÉ ·¥¶²¨± ɨ¢´Ò° ¸É·¥¸¸, ¢±²ÕÎ Ö
¶μ¢·¥¦¤¥´¨¥ ³ É·¨ÍÒ „Š, ¸´¨¦¥´¨¥ ¶Ê² ¤¥§μ±¸¨·¨¡μ´Ê±²¥μɨ¤É·¨Ëμ¸Ë Éμ¢ (¤’”) ¢ ·¥§Ê²ÓÉ É¥ ¨´£¨¡¨·μ¢ ´¨Ö £¨¤·μ±¸¨³μÎ¥¢¨´μ° (ƒŒ) ¡¨μ¸¨´É¥§ ¤’” ¨²¨ μ¸É ´μ¢±¨ ³ Ϩ´Ò ·¥¶²¨± ͨ¨ „Š-¸¢Ö§Ò¢ ÕШ³¨ ¡¥²± ³¨.
‚ S-Ë §¥ ¸¨£´ ²μ³, ±É¨¢¨·ÊÕШ³ Î¥±¶μ°´É, ¸²Ê¦¨É § ¸É·Ö¢Ï Ö ·¥¶²¨± ɨ¢´ Ö ¢¨²± [54]. ‘¥´¸μ· ³¨ ¢Ò¸Éʶ ÕÉ ¶μ²¨³¥· § Polε ¨ ¢§ ¨³μ¤¥°¸É¢ÊÕШ¥ ¸ ´¥° ¡¥²±¨ Dpb11 ¨ Drc1, É ±¦¥ £¥²¨± § Sgs1, ±μÉμ· Ö μ¡² ¤ ¥É
’” §´μ° ±É¨¢´μ¸ÉÓÕ ¨ ¸¢Ö§Ò¢ ¥É¸Ö ¸ · §¢¥É¢²¥´´Ò³¨ ¸É·Ê±ÉÊ· ³¨ „Š.
·¥¤¶μ² £ ¥É¸Ö, ÎÉμ μ´ ÊÎ ¸É¢Ê¥É ¢ Ëμ·³¨·μ¢ ´¨¨ ¸¨£´ ² ¶μ¸·¥¤¸É¢μ³ · §·¥Ï¥´¨Ö ¡¥·· ´É´ÒÌ ¸¶ ·¥´´ÒÌ ¤¢μ°´ÒÌ ¸¶¨· ²¥° [55]. ´ ¶·¨´ ¤²¥¦¨É
± Éμ° ¦¥ Ô¶¨¸É ɨΥ¸±μ° £·Ê¶¶¥ ¢ μÉ´μÏ¥´¨¨ ±É¨¢ ͨ¨ Rad53 ¢ ¶·¨¸Êɸɢ¨¨ ƒŒ, ÎÉμ ¨ Polε, ¨ ÔÉμÉ ¸¨£´ ²Ó´Ò° ¶ÊÉÓ ¤¥°¸É¢Ê¥É ¶ · ²²¥²Ó´μ Rad17
¨ Rad24 [56]. ¤´ ±μ ´¥ Ö¸´μ, ¤¥°¸É¢¨É¥²Ó´μ ²¨ S-¸¶¥Í¨Ë¨Î´Ò¥ ¸¥´¸μ·Ò
Polε ¨ Sgs1 ʧ´ ÕÉ ¶μ¢·¥¦¤¥´¨Ö „Š ¨²¨ ¨Ì ËÊ´±Í¨μ´¨·μ¢ ´¨¥ ¶·¨¢μ¤¨É
± μ¡· §μ¢ ´¨Õ μ¡Ð¨Ì ¨´É¥·³¥¤¨ Éμ¢, ¢ Éμ³ Î¨¸²¥ É ±¨Ì ± ± μ´„Š. ‚ μÉ¢¥É ´ ¶μ¢·¥¦¤¥´¨¥ „Š ±μ³¶²¥±¸ Rad6-Rad18 ³μ´μÊ¡¨±¢¨É¨´¨·Ê¥É ¸±·¥¶±Ê
PCNA (Pol30K164ub), μ¡²¥£Î Ö ¸¢Ö§Ò¢ ´¨¥ ¸ ¶μ²¨³¥· § ³¨ TLS (translesion
synthesis) ¤²Ö ¶·μÌ즤¥´¨Ö ¶μ¢·¥¦¤¥´¨Ö, ¡²μ±¨·ÊÕÐ¥£μ ·¥¶²¨± Í¨Õ [57].
„ ²Ó´¥°Ï¥¥ ¶μ²¨Ê¡¨±¢¨É¨´¨·μ¢ ´¨¥ Éμ£μ ¦¥ ¸ °É PCNA ±μ³¶²¥±¸μ³ Rad5Ubc13-Mms2 ±É¨¢¨·Ê¥É ¡¥§μϨ¡μδҰ ¶ÊÉÓ ¶¥·¥±²ÕÎ¥´¨Ö ·¥¶²¨± ͨ¨ ´ ´¥¶μ¢·¥¦¤¥´´ÊÕ ´¨ÉÓ Ì·μ³ É¨´ .
—¥±¶μ°´É ·¥¶²¨± ͨ¨ „Š ¢ μ¸´μ¢´μ³ ¨¸¶μ²Ó§Ê¥É É¥ ¦¥ ¸ ³Ò¥ ¡¥²±¨, ÎÉμ
¨ Î¥±¶μ°´É ¶μ¢·¥¦¤¥´¨° „Š. ƒ² ¢´μ¥ · §²¨Î¨¥ § ±²ÕÎ ¥É¸Ö ¢ ¨¸¶μ²Ó§μ¢ ´¨¨ · §´ÒÌ ³¥¤¨ Éμ·μ¢. ‚ ·¥¶²¨± ɨ¢´μ³ Î¥±¶μ°´É¥ ¢³¥¸Éμ Rad9 ¢ ± Î¥¸É¢¥
³¥¤¨ Éμ· ¢Ò¸Éʶ ¥É £¥É¥·μÉ·¨³¥·´Ò° ±μ³¶²¥±¸ Mrc1-Tof1-Csm3 (μ·Éμ²μ£¨
Ê ¶μ§¢μ´μδÒÌ Claspin, Timeless, Tipin ¸μμÉ¢¥É¸É¢¥´´μ). ‘ ·¥¶²¨¸μ³μ° ´¥¶μ¸·¥¤¸É¢¥´´μ ¸¢Ö§ ´Ò ¤¢ ¶·μÉμ³¥· Tof1 ¨ Csm3, ±μÉμ·Ò¥ μ¶μ¸·¥¤ÊÕÉ ¸¢Ö§Ò¢ ´¨¥ Mrc1 ¸ ·¥¶²¨± ɨ¢´μ° ¢¨²±μ° [58]. ɨ ¡¥²±¨ ¢§ ¨³μ¤¥°¸É¢ÊÕÉ ¸ ·¥¶²¨± ɨ¢´Ò³¨ ±μ³¶²¥±¸ ³¨ ¨ ¡¥²± ³¨ GINS, MCM, Cdc45, Polε [59]. ¥²μ±
Mrc1 μ¡²¥£Î ¥É ¶·μÍ¥¸¸ Ô²μ´£ ͨ¨ ·¥¶²¨± ͨ¨ ¢ ´¥¢μ§³ÊÐ¥´´ÒÌ Ê¸²μ¢¨ÖÌ,
É ±¦¥ ¢Ò¸Éʶ ¥É ¢ ·μ²¨ ³¥¤¨ Éμ· ·¥¶²¨± ɨ¢´μ£μ Î¥±¶μ°´É ¨ ´¥μ¡Ì줨³ ¤²Ö ¶¥·¥¤ Ψ ¸¨£´ ² μ ¶μ¢·¥¦¤¥´¨¨ „Š μÉ Œ¥¸1 ± Rad53 ¢ ¶·μÍ¥¸¸¥
·¥¶²¨± ɨ¢´μ£μ ¸É·¥¸¸ . μ¸±μ²Ó±Ê ³¥¤¨ Éμ· Mrc1 Ö¢²Ö¥É¸Ö Î ¸ÉÓÕ ·¥¶²¨¸μ³Ò ¨ ¤¢¨£ ¥É¸Ö ¸ ´¥° ¢ ¶·μÍ¥¸¸¥ ·¥¶²¨± ͨ¨ [60, 61], Éμ μ´ ´¥ ´Ê¦¤ ¥É¸Ö ¢
¸¶¥Í¨ ²Ó´μ° ¤μ¸É ¢±¥ ± § ¸É·Ö¢Ï¥° ·¥¶²¨± ɨ¢´μ° ¢¨²±¥. ‘ ¤·Ê£μ° ¸Éμ·μ´Ò,
¢ μ¶·¥¤¥²¥´´ÒÌ Ì·μ³μ¸μ³´ÒÌ ¸ °É Ì, ¢ ±μÉμ·ÒÌ ´¥£¨¸Éμ´μ¢Ò¥ ¡¥²±¨ É¥¸´μ
¸¢Ö§ ´Ò ¸ „Š, ¤²Ö ¸μμÉ¢¥É¸É¢ÊÕÐ¥£μ ·¥¸É ´¥μ¡Ì줨³Ò Tof1 ¨ Csm3, ´¥
Mrc1 [62].
7
Œ¥¤¨ Éμ· Mrc1 μ¸ÊÐ¥¸É¢²Ö¥É ³μ´¨Éμ·¨´£ ¶·μ¤¢¨¦¥´¨Ö ·¥¶²¨± ɨ¢´μ°
¢¨²±¨ ¨ ¥¥ μ¸É ´μ¢±Ê ¢ μÉ¢¥É ´ ·¥¶²¨± ɨ¢´Ò° ¸É·¥¸¸. ‘ ¤·Ê£μ° ¸Éμ·μ´Ò,
³¥¤¨ Éμ· ¢Ò¸Éʶ ¥É ¢ ± Î¥¸É¢¥ ³μ²¥±Ê²Ö·´μ£μ Ö±μ·Ö ¶·¨ ¶μ¸²¥¤ÊÕÐ¥° § £·Ê§±¥ ¸¥´¸μ·´ÒÌ ¨ ÔËË¥±Éμ·´ÒÌ ±¨´ §. ‘Í¥´ ·¨° ¶·¨¡²¨§¨É¥²Ó´μ ¸²¥¤ÊÕШ°: ·¥¶²¨± ɨ¢´ Ö ³ Ϩ´ Polε/Mrc1 ʧ´ ¥É ¶μ¢·¥¦¤¥´¨¥; ± § ¸É·Ö¢Ï¥°
¢¨²±¥ ·¥±·Êɨ·Ê¥É¸Ö ±¨´ § Œ¥¸1, ¢¥·μÖÉ´μ, ¶μ¸·¥¤¸É¢μ³ ¢§ ¨³μ¤¥°¸É¢¨Ö ¸
ÊÎ ¸É± ³¨ μ´„Š, ¶μ±·ÒÉÒ³¨ ±μ³¶²¥±¸ ³¨ RPA [61, 63]. ¡ ± ´μ´¨Î¥¸±¨Ì ±É¨¢ Éμ· ±¨´ §Ò Œ¥¸1 Å Ddc1 ¨ Dpb11 Å ³μ£ÊÉ ÊÎ ¸É¢μ¢ ÉÓ ¢ ·¥¶²¨± ɨ¢´μ³ Î¥±¶μ°´É¥ [64], ÌμÉÖ ´¥ Ö¸´μ, ¤¥°¸É¢¨É¥²Ó´μ ²¨ μ´¨ ¡¸μ²ÕÉ´μ
´¥μ¡Ì줨³Ò [21, 65]. ‚ § ¸É·Ö¢Ï¥° ·¥¶²¨± ɨ¢´μ° ¢¨²±¥ ±¨´ § Œ¥¸1 Ëμ¸Ëμ·¨²¨·Ê¥É ³¥¤¨ Éμ· Mrc1 [61], ±μÉμ·Ò° ¸μ¤¥·¦¨É 17 SQ/TQ-¸ °Éμ¢ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ±¨´ §μ° Œ¥¸1. μ-¢¨¤¨³μ³Ê, ¨§³¥´¥´¨Ö ±μ´Ëμ·³ ͨ¨ Mrc1
¢²¨ÖÕÉ ´ ¢§ ¨³μ¤¥°¸É¢¨¥ ¸ ±μ³¶μ´¥´É ³¨ ·¥¶²¨¸μ³Ò. μ± § ´μ, ÎÉμ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ Mrc1 ¶·¨¢μ¤¨É ± ¢Ò¸¢μ¡μ¦¤¥´¨Õ N-±μ´Í ¡μ²ÓÏμ° ¸Ê¡Ñ¥¤¨´¨ÍÒ Polε (Pol2), ´μ ¢§ ¨³μ¤¥°¸É¢¨¥ ³¥¦¤Ê Mrc1ph ¨ C-±μ´Íμ³ Pol2 ¸μÌ· ´Ö¥É¸Ö [66]. ¥²±¨ Mrc1 ¨ Mec1 ´¥μ¡Ì줨³Ò ¤²Ö ¸É ¡¨²¨§ ͨ¨ ¶μ²¨³¥· §
Polε ¨ Polα [67Ä69]. ¥²μ± Mrc1 ¨´£¨¡¨·Ê¥É μÉ¸μ¥¤¨´¥´¨¥ ·¥¶²¨± ɨ¢´μ°
£¥²¨± §Ò Mcm2-7 μÉ ¶μ²¨³¥· §Ò ´ ²¨¤¨·ÊÕÐ¥° ´¨É¨ ¨ § ¶¨· ¥É μ¡¥ ¶μ²μ¢¨´Ò ·¥¶²¨¸μ³Ò ¢ § ¸É·Ö¢Ï¥° ¢¨²±¥ [59]. ’ ±¨³ μ¡· §μ³, Ëμ¸Ëμ·¨²¨·μ¢ ´´Ò° ³¥¤¨ Éμ· Mrc1 ¸É ¡¨²¨§¨·Ê¥É § ¸É·Ö¢ÏÊÕ ·¥¶²¨¸μ³Ê, ±μÉμ· Ö μ¸É ¥É¸Ö
¸¢Ö§ ´´μ° ¸ ·¥¶²¨± ɨ¢´μ° ¢¨²±μ°, ¨ ʤ¥·¦¨¢ ¥É ±¨´ §Ê Œ¥¸1 ¢ μ¡² ¸É¨
§ ¸É·Ö¢Ï¥° ¢¨²±¨.
’ ±μ¥ ¢§ ¨³μ¤¥°¸É¢¨¥ ¸μ§¤ ¥É ¶² ÉËμ·³Ê ¤²Ö ¶μ¸²¥¤ÊÕÐ¨Ì ¸μ¡Òɨ° Î¥±¶μ°´É , ¢±²ÕÎ Ö ¤μ¸É ¢±Ê ¨ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ Rad53. ‘μ¢³¥¸É´ Ö ²μ± ²¨§ ꬅ Œ¥¸1 ¨ Mrc1 ¤μ¸É Éμδ ¤²Ö ·¥±·Êɨ·μ¢ ´¨Ö, Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ¨
±É¨¢ ͨ¨ Rad53 [70]. Mrc1 Ëμ¸Ëμ·¨²¨·Ê¥É¸Ö ´¥ Éμ²Ó±μ ±¨´ §μ° Mec1, ´μ ¨
Rad53 [60]. ±É¨¢ ꬅ Rad53 ¨ ¤μ¶μ²´¨É¥²Ó´μ¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ³¥¤¨ Éμ· Mrc1 ¶μ§¢μ²ÖÕÉ ¶μ¤¤¥·¦¨¢ ÉÓ ·¥¶²¨¸μ³Ê ¨ ·¥¶²¨± ɨ¢´ÊÕ ¢¨²±Ê ¤μ É¥Ì
¶μ·, ¶μ± ·¥¶²¨± ꬅ ´¥ ¢μ§μ¡´μ¢¨É¸Ö. ‘ÊÐ¥¸É¢Ê¥É ´¥¸±μ²Ó±μ ³¥Ì ´¨§³μ¢
¸É ¡¨²¨§ ͨ¨ ¢¨²±¨. Œ¥¸1 ¨ Rad53 ³μ£ÊÉ ËÊ´±Í¨μ´¨·μ¢ ÉÓ ´ · §´ÒÌ ¶ÊÉÖÌ
¸É ¡¨²¨§ ͨ¨ § ¸É·Ö¢Ï¥° ¢¨²±¨. Rad53 ¸É ¡¨²¨§¨·Ê¥É § ¸É·Ö¢ÏÊÕ ·¥¶²¨± ɨ¢´ÊÕ ¢¨²±Ê, Î ¸É¨Î´μ ¡²μ±¨·ÊÖ ±É¨¢´μ¸ÉÓ Exo1 [71]. Š·μ³¥ Éμ£μ, Rad53
¨³¥¥É Exo1-´¥§ ¢¨¸¨³ÊÕ ËÊ´±Í¨Õ [72]. Š¨´ § Rad53, ¶μ-¢¨¤¨³μ³Ê, Ö¢²Ö¥É¸Ö μ¸´μ¢´Ò³ ÊÎ ¸É´¨±μ³ ¸É ¡¨²¨§ ͨ¨ ¢¨²±¨. ¤´ ±μ ¢ μɸÊɸɢ¨¨ Rad53
¢ ¸É ¡¨²¨§ ͨ¨ ¢¨²±¨ ¶·¨´¨³ ¥É ÊÎ ¸É¨¥ ±¨´ § Chk1 [71].
‚ S-Ë §¥ ±²¥Éμδμ£μ ͨ±² ¸ÊÐ¥¸É¢Ê¥É ¤μ¶μ²´¨É¥²Ó´ Ö ·μ²Ó Ëμ¸Ëμ·¨²¨·μ¢ ´´ÒÌ £¨¸Éμ´μ¢ 2S129ph ¢ ¸¡μ·±¥ ±μ£¥§¨´μ¢ÒÌ ±μ³¶²¥±¸μ¢ ¢ ¸ °É¥
„. ‚ ´μ·³¥ ±μ£¥§¨´μ¢Ò° ±μ³¶²¥±¸ ¸±·¥¶²Ö¥É ¸¥¸É·¨´¸±¨¥ Ì·μ³ É¨¤Ò ¢ ³¥¸É Ì, · §¤¥²¥´´ÒÌ · ¸¸ÉμÖ´¨¥³ μ±μ²μ 10Ä15 É. ¶. ´. ¤´ ±μ ±μ£¤ ¢ μ¤´μ° ¨§
Ì·μ³ É¨¤ ¶μÖ¢²Ö¥É¸Ö „, ¸ μ¡¥¨Ì ¸Éμ·μ´ „ ¸μ¡¨· ¥É¸Ö ³´μ¦¥¸É¢μ ±μ£¥§¨´μ¢ÒÌ ±μ³¶²¥±¸μ¢, ¸¢Ö§Ò¢ ÕÐ¨Ì · §μ·¢ ´´ÊÕ ¨ ´ ɨ¢´ÊÕ Ì·μ³ É¨¤Ò. ·¨
ÔÉμ³ ·μ²Ó Ëμ¸Ëμ·¨²¨·μ¢ ´´μ£μ £¨¸Éμ´ 2S129ph ¸μ¸Éμ¨É ¢ Éμ³, ÎÉμ¡Ò
8
¸¢Ö§ ÉÓ ¢ ¸ °É¥ „ ¸¶¥Í¨ ²¨§¨·μ¢ ´´Ò¥ ¡¥²±¨ (Csm3, Tof1, Mrc1, Rad9,
Ddc1), ÊÎ ¸É¢ÊÕШ¥ ¢ μ·£ ´¨§ ͨ¨ ±μ£¥§¨¨ Ì·μ³ É¨¤ [73]. ‚μ§´¨±´μ¢¥´¨¥
±μ£¥§¨´μ¢μ£μ ¤μ³¥´ ¢μ±·Ê£ „ μ¡²¥£Î ¥É ¶μ¨¸± £μ³μ²μ£¨¨ ¶·¨ ·¥¶ · ͨ¨
„ ¶ÊÉ¥³ £μ³μ²μ£¨Î´μ° ·¥±μ³¡¨´ ͨ¨ HR (homologous recombination), ¸¨£´ ²μ³ ¤²Ö ¶¥·¥¸É·μ°±¨ ±μ£¥§¨´μ¢μ£μ ±μ³¶²¥±¸ ¸²Ê¦¨É Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ £¨¸Éμ´ 2S129ph [74].
Š’ˆ‚–ˆŸ —…Š‰’
„·μ¦¦¥¢ Ö ±²¥É± , ¸Éμ²±´Ê¢Ï Ö¸Ö ¸ ¶μ¢·¥¦¤¥´¨¥³ ¢ G1, § ³¥¤²Ö¥É ´ 20Ä30 ³¨´ ¢¸Éʶ²¥´¨¥ ¢ Ë §Ê S. “ ¤·μ¦¦¥° μ¸É ´μ¢± ¢ G1/S, ¶μ-¢¨¤¨³μ³Ê,
μ¡¥¸¶¥Î¨¢ ¥É ¢·¥³Ö ¤²Ö ·¥¶ · ͨ¨ [75], Ê ³²¥±μ¶¨É ÕÐ¨Ì Å ¤²Ö § ¶Ê¸± ¶μ¶Éμ§ . É § ¤¥·¦± §´ Ψɥ²Ó´μ ±μ·μÎ¥, Î¥³ μ¶μ¸·¥¤μ¢ ´´ Ö Î¥±¶μ°´Éμ³ μ¸É ´μ¢± ¢ G2/M ¶·μ¤μ²¦¨É¥²Ó´μ¸ÉÓÕ ¤μ 8 Î. ’ ±, ¶·¨ ¨´¤Ê±Í¨¨
-Ô´¤μ´Ê±²¥ §μ° ¥¤¨´¨Î´μ£μ „ ¶·μ¨¸Ìμ¤¨É Œ¥¸1-§ ¢¨¸¨³ Ö ±μ·μɱ Ö
§ ¤¥·¦± ¢ G1 (15 ³¨´) ¨ ¤²¨É¥²Ó´ Ö § ¤¥·¦± (8Ä12 Î) ¢ G2 ¶¥·¥¤ ´ Ë §μ°, ´μ ´¥ ´ ¡²Õ¤ ¥É¸Ö § ¤¥·¦±¨ ¢ Ë §¥ S ¨²¨ ±É¨¢ ͨ¨ S-§ ¢¨¸¨³μ£μ
Î¥±¶μ°´É [76]. ‚μ§³μ¦´μ, ÔÉ · §´¨Í ¸¢Ö§ ´ ¸ É¥³, ÎÉμ ¢ G2/M ¤μ¸Éʶ¥´
¡μ²¥¥ Ϩ·μ±¨° ¸¶¥±É· ɨ¶μ¢ ·¥¶ · ͨ¨, ¢ Éμ³ Î¨¸²¥ ³¥¦Ì·μ³ ɨ¤´Ò° μ¡³¥´ HR. ‚ G1 „ ·¥¶ ·¨·Ê¥É¸Ö ¶μ ³¥Ì ´¨§³Ê μ¡Ñ¥¤¨´¥´¨Ö ±μ´Íμ¢ NHEJ
(nongomologous end joining), ´¥ É·¥¡ÊÕÐ¥³Ê ¶·μÉÖ¦¥´´ÒÌ ÊÎ ¸É±μ¢ μ´„Š,
¸²¥¤μ¢ É¥²Ó´μ, ¨ ¨´É¥´¸¨¢´μ° ·¥§¥±Í¨¨.
‚ Ë §¥ G1 ³ Ϩ´ ·¥¶ · ͨ¨ · §²¨Î ¥É · §´Ò¥ ɨ¶Ò · §·Ò¢μ¢, ±μÉμ·Ò¥
É· ´¸²¨·ÊÕÉ¸Ö ¢ · §²¨Î´Ò¥ ³μ¤Ò ·¥¶ · ͨ¨ ¨ Î¥±¶μ°´É- ±É¨¢ ͨ¨ ¢ G1 ¨
S/G2 ±²¥É± Ì. §·Ò¢Ò ¢ ÊÎ ¸É± Ì „Š, ¸¢Ö§ ´´ÒÌ ¸ ´Ê±²¥μ¸μ³μ°, μ¡· §ÊÕÉ ±μ·μɱ¨¥ Ë· £³¥´ÉÒ μ´„Š. ‚ Éμ ¦¥ ¢·¥³Ö · §·Ò¢Ò ¢ ²¨´±¥·´ÒÌ
ÊÎ ¸É± Ì μ¡· §ÊÕÉ ¡μ²¥¥ ¶·μÉÖ¦¥´´Ò¥ Ë· £³¥´ÉÒ μ´„Š. ‚ ¸²ÊÎ ¥ ÉʶÒÌ,
´¥³μ¤¨Ë¨Í¨·μ¢ ´´ÒÌ ¨²¨ ²¨¶±¨Ì ±μ´Íμ¢, É ±¦¥ ¶·μ¸Éμ£μ · §·Ò¢ ¸ μ¡· §μ¢ ´¨¥³ ±μ·μɱ¨Ì 3 - ¨ 5 -μ¤´μ´¨É¥¢ÒÌ ±μ´Íμ¢ ·¥¶ · ꬅ „ μ¸ÊÐ¥¸É¢²Ö¥É¸Ö ¶ÊÉ¥³ NHEJ [77]. ‘ ±μ´Í ³¨ ¸¢Ö§Ò¢ ¥É¸Ö ±μ³¶²¥±¸ Ku70/Ku80, ¨
¶·μ¨¸Ìμ¤¨É ¶·Ö³μ¥ ¢μ¸¸μ¥¤¨´¥´¨¥ ±μ´Íμ¢. „²Ö NHEJ ´¥ É·¥¡Ê¥É¸Ö ¨´¤Ê±Í¨Ö
Ô±¸¶·¥¸¸¨¨ ¡¥²±μ¢, É ± ± ± Ku-¡¥²±¨ ¤¥¶μ´¨·μ¢ ´Ò ¢ É¥²μ³¥·´ÒÌ ÊÎ ¸É± Ì Ì·μ³μ¸μ³ ¨ ¶¥·¥· ¸¶·¥¤¥²ÖÕÉ¸Ö ¶·¨ ¶μÖ¢²¥´¨¨ · §·Ò¢μ¢. …¸²¨ ±μ´ÍÒ
„ „Š ´¥ μ¡² ¤ ÕÉ ¸¢μ°¸É¢ ³¨, ¶μ¤Ìμ¤ÖШ³¨ ¤²Ö ¡Ò¸É·μ£μ ¢μ¸¸μ¥¤¨´¥´¨Ö, ¢ ¶·μÍ¥¸¸ ·¥¶ · ͨ¨ ¢μ¢²¥± ÕÉ¸Ö ´Ê±²¥ §Ò Sae2 ¨ Pso2 (Ê Î¥²μ¢¥± £μ³μ²μ£ Artemis). 쳨³μ Ku ¸ ±μ´Í ³¨ „ ³μ¦¥É ¸¢Ö§Ò¢ ÉÓ¸Ö ´Ê±²¥ §´Ò° ±μ³¶²¥±¸ MRX-Sae2, μ¸ÊÐ¥¸É¢²ÖÕШ° ´¥¡μ²ÓÏμ° ¶·μÍ¥¸¸¨´£ (1Ä2 ´.).
Ku-£¥É¥·μ¤¨³¥· ¨´£¨¡¨·Ê¥É ¶·μÍ¥¸¸¨´£ „Š Ô±§μ´Ê±²¥ § ³¨ ¨ § ³¥¤²Ö¥É ¸±μ·μ¸ÉÓ ¶·μÍ¥¸¸¨´£ ±μ³¶²¥±¸μ³ MRX. ‡ μ´„Š ¸ ±μ³¶²¥±¸μ³ MRX ±μ´±Ê·¨·ÊÕÉ ¡¥²±¨ RPA, ±μÉμ·Ò¥ ¸¢Ö§Ò¢ ÕÉ¸Ö ¸ μ´„Š ¤²¨´´ÒÌ, ¶·μÍ¥¸¸¨·ÊÕÐ¨Ì¸Ö ±μ´Íμ¢, ¨ ±É¨¢¨·ÊÕÉ Î¥±¶μ°´É. …¸²¨ ·¥§¥±Í¨Ö ±μ´Íμ¢ „
9
¤μ¸É¨£ ¥É ¤²¨´Ò ¡μ²¥¥ Î¥ÉÒ·¥Ì ´Ê±²¥μɨ¤μ¢, ¤²Ö ·¥¶ · ͨ¨ ´¥μ¡Ì줨³Ò
¢¥É¢¨ HR.
‚ G1 ¡μ²ÓÏ Ö Î ¸ÉÓ „, ¨´¤Êͨ·μ¢ ´´ÒÌ ˆ, ÔËË¥±É¨¢´μ ¶·μÍ¥¸¸¨·Ê¥É¸Ö, ¶μ¤£μÉ ¢²¨¢ Ö¸Ó ± HR, ¨ ¸¢Ö§Ò¢ ¥É¸Ö ¸ Rfa1. ‚ Éμ ¦¥ ¢·¥³Ö · §·Ò¢Ò,
¨´¤Êͨ·Ê¥³Ò¥ -Ô´¤μ´Ê±²¥ §μ°, ʧ´ ÕÉ¸Ö Rfa1 Éμ²Ó±μ ¶μ¸²¥ ¢¸Éʶ²¥´¨Ö ¢
Ë §Ê S, ¨ ÔÉμ § ¢¨¸¨É μÉ ±μ³¶²¥±¸ Ku, ¸¢Ö§ ´´μ£μ ¸ ±μ´Í ³¨ „. ¤´ ±μ
¶μ¸²¥¤ÊÕШ¥ ¸É ¤¨¨ HR, ¸¢Ö§ ´´Ò¥ ¸ Rad52, ¨´£¨¡¨·μ¢ ´Ò ¢ G1. „ ²¥¥ ¢
¶·μÍ¥¸¸¥ ±²¥Éμδμ£μ ͨ±² ¶·μ¨¸Ìμ¤¨É ±É¨¢ ꬅ HR ¢ ·¥§Ê²ÓÉ É¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö Rad52 ±¨´ §μ° CDK1. ¥±·Êɨ·μ¢ ´¨¥ Rad52 μ¸ÊÐ¥¸É¢²Ö¥É¸Ö
Éμ²Ó±μ ¶μ¸²¥ ¢¸Éʶ²¥´¨Ö ¢ Ë §Ê S [78]. Rad52 ±μ´¸É¨ÉÊɨ¢´μ Ëμ¸Ëμ·¨²¨·Ê¥É¸Ö ¶μ ´¥¸±μ²Ó±¨³ ¸ °É ³ ¸¥·¨´μ¢ÒÌ ¨ É·¥μ´¨´μ¢ÒÌ μ¸É ɱμ¢. ·¨
¢¸Éʶ²¥´¨¨ ¢ Ë §Ê S ¶·μ¨¸Ìμ¤¨É ¤μ¶μ²´¨É¥²Ó´μ¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥. ”μ¸Ëμ·¨²¨·Ê¥É¸Ö ‘-±μ´¥Í, ÌμÉÖ ±μ´±·¥É´Ò¥ μ¸É ɱ¨ ¨ Ë¥´μɨ¶¨Î¥¸±¨° ÔËË¥±É
μɸÊɸɢ¨Ö Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ¥Ð¥ ¶·¥¤¸Éμ¨É ¢ÒÖ¸´¨ÉÓ. μ¸²¥ ¶μ¢·¥¦¤¥´¨Ö
„Š ¤μ¶μ²´¨É¥²Ó´μ£μ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ´¥ ¶·μ¨¸Ì줨É. ·¨Î¥³ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ´¥ § ¢¨¸¨É μÉ Mec1 ¨ Tel1, ÎÉμ ¶μ¤Î¥·±¨¢ ¥É ¥£μ ´¥§ ¢¨¸¨³μ¸ÉÓ
μÉ ¶μ¢·¥¦¤¥´¨° „Š. ±É¨¢´μ¸ÉÓ CDK1 ´¥μ¡Ì줨³ ¤²Ö ·¥±·Êɨ·μ¢ ´¨Ö
Rad52 ¢ Ëμ±Ê¸Ò [79], μ¤´ ±μ ´¥ Ö¸´μ, ¤¥°¸É¢¨É¥²Ó´μ ²¨ CDK1 ´ ¶·Ö³ÊÕ
μÉ¢¥É¸É¢¥´´ § ͨ±²μ§ ¢¨¸¨³μ¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ [80]. •μÉÖ ¤¥²¥Í¨¨ ±É¨¢ Éμ·μ¢ CDK1 ͨ±²¨´μ¢ S-Ë §Ò CLB5 ¨ CLB6 (‚-ɨ¶) § ³¥¤²ÖÕÉ ·¥±·Êɨ·μ¢ ´¨¥ ·¥±μ³¡¨´ Í¨μ´´μ£μ ¡¥²± , ´μ ´¥ ¨¸±²ÕÎ¥´μ, ÎÉμ CDK1 Ëμ¸Ëμ·¨²¨·Ê¥É ¢ÒÏ¥¸ÉμÖШ° Ë ±Éμ·, ´ ¶·¨³¥·, RPA. ’ ± ¦¥ ± ± ¨ Rad52, Rfa2
Ëμ¸Ëμ·¨²¨·Ê¥É¸Ö ¸¶μ¸μ¡μ³, § ¢¨¸¨³Ò³ μÉ ¶·μÌ즤¥´¨Ö ±²¥Éμδμ£μ ͨ±² ¨
¢ μÉ¢¥É ´ £¥´μÉμ±¸¨Î´Ò° ¸É·¥¸¸ [79, 81, 82]. ’ ±¨³ μ¡· §μ³, ¶·μÉÖ¦¥´´ Ö
·¥¸¥±Í¨Ö ¨ ·¥±·Êɨ·μ¢ ´¨¥ Rad52 ¨´¨Í¨¨·ÊÕÉ¸Ö ¶·¨ ¶·μÌ즤¥´¨¨ G1/S ¨
·¥£Ê²¨·ÊÕÉ¸Ö ±¨´ §μ° CDK1. ‚μ§³μ¦´ Ö ·μ²Ó ³μ¤¨Ë¨Í¨·μ¢ ´´μ£μ Rad52
¢ μÉ¢¥É ´ ¶μ¢·¥¦¤¥´¨¥ § ±²ÕÎ ¥É¸Ö ¢ ·¥²μ± ²¨§ ͨ¨ Rad52 ¨§ ¤¨ËËʧ´μ£μ
Ö¤¥·´μ£μ · ¸¶·¥¤¥²¥´¨Ö ¢ μɤ¥²Ó´Ò¥ Ëμ±Ê¸Ò ¢ ¸ °É Ì „. ‚μ§³μ¦´μ, ÎÉμ
´ Î ²Ó´Ò° Ê·μ¢¥´Ó Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö, μ¡´ ·Ê¦¨¢ ¥³Ò° ¶·¨ ¶·μÌ즤¥´¨¨
±²¥Éμδμ£μ ͨ±² , ´¥£ ɨ¢´μ ·¥£Ê²¨·Ê¥É Ëμ±Ê¸Ò Rad52, ±²¥Éμδμ-§ ¢¨¸¨³μ¥
Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ μ¡¥¸¶¥Î¨¢ ¥É μ¡· §μ¢ ´¨¥ Ëμ±Ê¸μ¢ ¤²Ö HR.
Œ¥Ì ´¨§³Ò ±É¨¢ ͨ¨ Î¥±¶μ°´Éμ¢ ¢ G1 ¨ G2 É ±¦¥ μɲ¨Î ÕɸÖ. ±É¨¢ Í¨Ö Î¥±¶μ°´É „ ¢ Ë §¥ G1 ´¥ ´Ê¦¤ ¥É¸Ö ¢ CDK1 [83], ¨³¥ÕÐ¥° ¢ ÔÉμ°
Ë §¥ ´¨§±ÊÕ ±É¨¢´μ¸ÉÓ. ¤´ ±μ ¢ Ë § Ì G2/Œ ÔËË¥±É¨¢´μ¥ Ëμ·³¨·μ¢ ´¨¥
¸¨£´ ² Î¥±¶μ°´É ´Ê¦¤ ¥É¸Ö ¢ ±É¨¢´μ¸É¨ CDK1, ¨ Î ¸É¨Î´μ ÔÉμ ¸¢Ö§ ´μ
¸ ÊÎ ¸É¨¥³ CDK1 ¢ ¶·μÍ¥¸¸¨´£¥ „ [83Ä86]. CDK1 Ëμ¸Ëμ·¨²¨·Ê¥É S267
´Ê±²¥ §Ò Sae2, Ëμ·³¨·ÊÕÐ¥° ÊÎ ¸Éμ± μ´„Š [87] ¨ ´¥μ¡Ì줨³μ° ¤²Ö ±É¨¢ ͨ¨ Î¥±¶μ°´É [83]. ‚Éμ·μ° ³¨Ï¥´ÓÕ ±¨´ §Ò CDK1 Ö¢²Ö¥É¸Ö ´Ê±²¥ § Dna2,
Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ±μÉμ·μ° μ¡¥¸¶¥Î¨¢ ¥É ¥¥ ¤μ¸É ¢±Ê ¢ Ö¤·μ [88]. ʱ²¥ § Sae2 μ¡· §Ê¥É ±μ·μɱ¨¥ ÊÎ ¸É±¨ μ´„Š, ¤²Ö Ëμ·³¨·μ¢ ´¨Ö ¡μ²¥¥ ¶·μÉÖ¦¥´´ÒÌ Ë· £³¥´Éμ¢ É·¥¡Ê¥É¸Ö ÊÎ ¸É¨¥ ´Ê±²¥ § Dna2 ¨ Exo1, ±μ³¶²¥±¸ MRX ¨
£¥²¨± §Ò Sgs1.
10
•μÉÖ ·¥§¥±Í¨Ö ¨£· ¥É ¢ ¦´ÊÕ ·μ²Ó ¢ ʸ¨²¥´¨¨ ¸¨£´ ² , ¡Ò²μ ¶μ± § ´μ,
ÎÉμ CDK1 ´¥μ¡Ì줨³ É ±¦¥ ¤²Ö ¶μ¸²¥¤ÊÕÐ¨Ì Ï £μ¢ ·¥±·Êɨ·μ¢ ´¨Ö ¸¥´¸μ·μ¢ ¨ ¤ ¶Éμ·μ¢. „²Ö ÔËË¥±É¨¢´μ° ¶¥·¥¤ Ψ ¸¨£´ ² Î¥±¶μ°´É ´¥μ¡Ì줨³Ò
PCNA-¶μ¤μ¡´ Ö ¸±·¥¶± Ddc1-Mec3-Rad17 ¨ ±¨´ § Mec1-Ddc2. Ò²μ ¶μ± § ´μ, ÎÉμ ¢ ¸¨´Ì·μ´´ÒÌ ±Ê²ÓÉÊ· Ì μ´¨ ¸¢Ö§Ò¢ ÕÉ¸Ö ¸ RPA ´¥§ ¢¨¸¨³μ
¤·Ê£ μÉ ¤·Ê£ [89Ä92], ¨ ¤²Ö ±É¨¢ ͨ¨ Î¥±¶μ°´É μ´¨ ´¥μ¡Ì줨³Ò ¨ ¤μ¸É ÉμÎ´Ò [93]. ¤´ ±μ ¢ G1 ¤²Ö ·¥±·Êɨ·μ¢ ´¨Ö Mec1-Ddc2 ± „ ´¥μ¡Ì줨³μ
¶·¥¤¢ ·¨É¥²Ó´μ¥ ¸¢Ö§Ò¢ ´¨¥ ¸±·¥¶±¨ Ddc1-Mec3-Rad17 ¸ RPA [94]. ‚ S/G2
¤²Ö ·¥±·Êɨ·μ¢ ´¨Ö Mec1-Ddc2 ¤μ¶μ²´¨É¥²Ó´μ ± RPA ¨ Ddc1-Mec3-Rad17
É·¥¡Ê¥É¸Ö ±É¨¢´ Ö ±¨´ § CDK1, ±μÉμ· Ö ¸ ³ ¶μ ¸¥¡¥ ´¥¤μ¸É Éμδ ¤²Ö ±É¨¢ ͨ¨ Î¥±¶μ°´É . ‚ Ë §¥ S, ±μ£¤ ±É¨¢´μ¸ÉÓ CDK1 ¤μ¸É ÉμÎ´μ ¢Ò¸μ± ,
´¥μ¡Ì줨³μ É ±¦¥ ¶·¨¸Êɸɢ¨¥ ±μ³¶²¥±¸ Ddc1-Mec3-Rad17. •μÉÖ Ê ³ÊÉ ´É mec3Δ ¢ μÉ¢¥É ´ μ¡²ÊÎ¥´¨¥ ˆ μ¡· §ÊÕÉ¸Ö Ëμ±Ê¸Ò Ddc2, ¶μ¸²¥¤ÊÕШ¥
ÔÉ ¶Ò Î¥±¶μ°´É ´¥ ±É¨¢¨·ÊÕɸÖ. ‚ ¸²ÊÎ ¥ ¨¸±Ê¸¸É¢¥´´μ° ±μ²μ± ²¨§ ͨ¨
±μ³¶²¥±¸μ¢ Mec1-Ddc2 ¨ Ddc1-Mec3-Rad17 ±¨´ § CDK1 ¢¸¥ ¥Ð¥ ¡Ò² ´¥μ¡Ì줨³ ¤²Ö ¶¥·¥¤ Ψ ¸¨£´ ² Î¥±¶μ°´É μÉ ¸¥´¸μ·μ¢ (Mec1-Ddc2 ¨ Ddc1Mec3-Rad17) ± ÔËË¥±Éμ·´μ° ±¨´ §¥ (Rad53) [94]. ‚ μɸÊɸɢ¨¨ Ddc1-Mec3Rad17 ´¥ ¶·μ¨¸Ìμ¤¨É Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö Rad53, ÎÉμ ¤¥³μ´¸É·¨·Ê¥É ¡¸μ²ÕÉ´ÊÕ ´¥μ¡Ì줨³μ¸ÉÓ ¸±·¥¶±¨ ¤²Ö ±É¨¢ ͨ¨ Œ¥¸1, ¤ ¦¥ ¥¸²¨ Ddc2 ¤μ¸É ¢²¥´
¢ Ëμ±Ê¸ ¶·¨ ¶·μÌ즤¥´¨¨ S/G2. RPA ´¥μ¡Ì줨³ ´¥ Éμ²Ó±μ ¤²Ö ·¥±·Êɨ·μ¢ ´¨Ö, ´μ ¨ ¤²Ö ʤ¥·¦ ´¨Ö ±μ³¶²¥±¸μ¢ Ddc1-Mec3-Rad17 ¨ Mec1-Ddc2 ¢
¸ °É¥ ¶μ¢·¥¦¤¥´¨Ö. μ-¢¨¤¨³μ³Ê, ±μ³¶²¥±¸Ò CDK1, Ddc1-Mec3-Rad17 ¨
RPA ±μ춥·¨·ÊÕÉ ¶·¨ ±É¨¢ ͨ¨ Î¥±¶μ°´É ¢ S/G2. ˆ´Ò³¨ ¸²μ¢ ³¨, ¤²Ö
±É¨¢ ͨ¨ Rad53 ¡¸μ²ÕÉ´μ ´¥μ¡Ì줨³ ±μ³¶²¥±¸ Ddc1-Mec3-Rad17, ¨ ±¨´ §´ Ö ±É¨¢´μ¸ÉÓ CDK1 μÉ¢¥É¸É¢¥´´ § ´¥§ ¢¨¸¨³μ¥ μÉ Ddc1-Mec3-Rad17
·¥±·Êɨ·μ¢ ´¨¥ Ddc2 ¢ S/G2 [93]. ´ ²¨§ £¨¡¥²¨ ±²¥Éμ± ¶·¨ μ¡²ÊÎ¥´¨¨ ˆ
¶μ± § ², ÎÉμ CD‘28/CDK1 ¢§ ¨³μ¤¥°¸É¢Ê¥É Ô¶¨¸É ɨΥ¸±¨ ¸ £¥´ ³¨ RAD17
(¸±·¥¶± Ddc1-Mec3-Rad17), RAD24 (§ £·Ê¦ ÕШ° ¸±·¥¶±Ê ±μ³¶²¥±¸ Rad24RFC), RAD9 (³¥¤¨ Éμ· Rad53), ´μ ¤¤¨É¨¢´μ ¸ RAD53 [95].
Š·μ³¥ Éμ£μ, CDK1 ¨£· ¥É ¢ ¦´ÊÕ ·μ²Ó ¢ Ëμ·³¨·μ¢ ´¨¨ Rad9 ¢ ± Î¥¸É¢¥
³¥¤¨ Éμ· Î¥±¶μ°´É ¶μ¢·¥¦¤¥´¨° „Š. Rad9 ¸μ¤¥·¦¨É 9 ¶μ²´ÒÌ (S/T-Px-K/R) ¨ 11 Î ¸É¨Î´ÒÌ (S/T-P) ±μ´¸¥´¸Ê¸μ¢ ±¨´ §Ò CDK1 (³ ±¸¨³ ²Ó´μ¥
Ψ¸²μ ¢ ¶·μÉ¥μ³¥ ¤·μ¦¦¥°) [96, 80]. Œ ¸¸-¸¶¥±É·μ³¥É·¨Î¥¸±¨° ´ ²¨§ ¶μ¤É¢¥·¤¨² Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ 15 ±μ´¸¥´¸Ê¸μ¢ in vivo [97, 98, 53]. ŒÊÉ Í¨μ´´Ò¥
§ ³¥´Ò 18 CDK1-¸ °Éμ¢ ¢ ¡¥²±¥ Rad9 ¢Ò§Ò¢ ÕÉ ÊÉ· ÉÊ ¤ ¶Éμ·´μ° ËÊ´±Í¨¨ ¨
´¥¸¶μ¸μ¡´μ¸ÉÓ ±É¨¢¨·μ¢ ÉÓ ±¨´ §Ê Rad53. ±É¨¢ ꬅ Rad9 ¢±²ÕÎ ¥É ³´μ£μ
ÔÉ ¶μ¢, ¢ Éμ³ Î¨¸²¥ ·¥±·Êɨ·μ¢ ´¨¥ Rad9 ± ¶μ¢·¥¦¤¥´¨Õ „Š, ¨§³¥´¥´¨¥
¸É Éʸ 첨£μ³¥·¨§ ͨ¨, Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ±¨´ §μ° Œ¥¸1/Tel1, ¸¢Ö§Ò¢ ´¨¥
¨ ±É¨¢ Í¨Õ Rad53 [99, 38, 35]. ‚ ¤ ²Ó´¥°Ï¨Ì ¨¸¸²¥¤μ¢ ´¨ÖÌ ¶·¥¤¸Éμ¨É ¢ÒÖ¸´¨ÉÓ, ´ ± ±¨Ì ÔÉ ¶ Ì ¨³¥¥É §´ Î¥´¨¥ CDK1-§ ¢¨¸¨³μ¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥
Rad9. ´ ²μ£¨Î´μ Ê S. pombe ¶μ± § ´μ, ÎÉμ BRCT-¸μ¤¥·¦ Ш° Î¥±¶μ°´É´Ò°
¡¥²μ± Crb2 μ·Éμ²μ£ Rad9 ¶μ¤¢¥·£ ¥É¸Ö CD‘2-Ëμ¸Ëμ·¨²¨·μ¢ ´¨Õ [100Ä102],
11
¨ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ¢ ¦´μ ¤²Ö ²μ± ²¨§ ͨ¨ Crb2 [101]. ·¥¤¶μ² £ ¥É¸Ö,
ÎÉμ ÔÉμ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ´¥μ¡Ì줨³μ ¤²Ö ¤ ¶É ͨ¨ Î¥±¶μ°´É ¨ ·¥¶ · ͨ¨ [100, 102].
μ± § ´μ, ÎÉμ ¸ °ÉÒ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö Rad9 ÊÎ ¸É¢ÊÕÉ ¢μ ¢§ ¨³μ¤¥°¸É¢¨¨ ¸ ¡¥²±μ³ Dpb11, ±μÉμ·Ò° ·¥±·Êɨ·Ê¥É¸Ö ±μ³¶²¥±¸μ³ Ddc1-Mec3Rad17 [22]. Rad9 ³μ¦¥É ¢§ ¨³μ¤¥°¸É¢μ¢ ÉÓ ¸ Dpb11 ²¨¡μ ´ ¶·Ö³ÊÕ ¶μ¸·¥¤¸É¢μ³ T462ph ¨ T474ph [103], ²¨¡μ ±μ¸¢¥´´μ ¶μ¸·¥¤¸É¢μ³ S11ph [104].
‚§ ¨³μ¤¥°¸É¢¨¥ Dpb11 ¸ Rad9Ser11ph ¤¥É¥±É¨·Ê¥É¸Ö Éμ²Ó±μ ¶μ¸²¥ ¶μ¢·¥¦¤¥´¨Ö „Š.
É ±¨´ §Ò CDK1 § ¢¨¸¨É ¢ μ¸´μ¢´μ³ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ N-±μ´Í¥¢μ£μ
Ë· £³¥´É Rad9 (1Ä231 μ¸É.). ‚ ´¥³ ¸μ¸·¥¤μÉμÎ¥´μ μ±μ²μ ¶μ²μ¢¨´Ò (9 ¨§ 20)
±μ´¸¥´¸Ê¸μ¢ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ±¨´ §μ° CDK1 (CDK1-9) [105]. ÉμÉ Ë· £³¥´É μ¡μ§´ Ψ²¨ ± ± CAD (Chk1 activation domain). ‘ °ÉÒ CDK1-9 ËÊ´±Í¨μ´¨·ÊÕÉ ¸¶¥Í¨Ë¨Î¥¸±¨ ¢ μÉ´μÏ¥´¨¨ ¢Éμ·μ° ÔËË¥±Éμ·´μ° ±¨´ §Ò Chk1
¢ μÉ¢¥É ´ ¶μ¢·¥¦¤¥´¨Ö „Š ¨ ´¥μ¡Ì줨³Ò ¤²Ö ¨´¨Í¨ ͨ¨ ¨ ¶μ¤¤¥·¦ ´¨Ö
±É¨¢´μ¸É¨ Chk1 ¤²Ö ¢¸¥Ì ɨ¶μ¢ „Š-É·μ¶´ÒÌ £¥´Éμ¢. ¶μ³´¨³, ÎÉμ ¤²Ö
G2/M ·¥¸É ´¥μ¡Ì줨³Ò ¤¢ ¤¤¨É¨¢´ÒÌ ¶Êɨ, § ¢¨¸ÖÐ¨Ì μÉ ÔËË¥±Éμ·´ÒÌ
±¨´ § Rad53 ¨ Chk1 [106, 107]. ‚μ§³μ¦´μ, ¶μÔÉμ³Ê CDC28 ¢§ ¨³μ¤¥°¸É¢Ê¥É
¤¤¨É¨¢´μ ¸ RAD53 ¶·¨ μ¡²ÊÎ¥´¨¨ ˆ.
ɳ¥É¨³, ÎÉμ ³¥¤¨ Éμ· Rad9 ¶μ¤¢¥·£ ¥É¸Ö CDK1-§ ¢¨¸¨³μ³Ê Ëμ¸Ëμ·¨²¨·μ¢ ´¨Õ ¢ ¶·μÍ¥¸¸¥ ±²¥Éμδμ£μ ͨ±² ¢ μɸÊɸɢ¨¨ ¶μ¢·¥¦¤¥´¨° „Š [99,
108, 109]. ·¨ ÔÉμ³ ¶μ ³¥·¥ ¶·μÌ즤¥´¨Ö ±²¥Éμδμ£μ ͨ±² Î¥·¥§ S, G2
¨ Œ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ Rad9 ¢μ§· ¸É ¥É. ‚ ¶·μÍ¥¸¸ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ¢μ¢²¥Î¥´Ò ¢¸¥ Ëμ·³Ò Cdc28/Clb. ‚ Ë § Ì S ¨²¨ Œ ´ ¡²Õ¤ ¥É¸Ö ¶μ¤¢¨¦´ Ö
Ëμ·³ Rad9 ∼ 180Ä220 ±„ (C-Rad9). ·¨ ¶μ¢·¥¦¤¥´¨¨ „Š μ¡· §ÊÕɸÖ
¡μ²¥¥ ±·Ê¶´Ò¥ Ëμ·³Ò Rad9 (D-Rad9) [99, 108Ä110].
μ-¢¨¤¨³μ³Ê, ¸ÊÐ¥¸É¢Ê¥É ¤¨´ ³¨Î¥¸± Ö ¸¸μͨ ꬅ Rad9 ¨ Chk1 ¸ Ì·μ³ É¨´μ³, ¤ ¦¥ ¢ μɸÊɸɢ¨¨ ¶μ¢·¥¦¤¥´¨° „Š [107, 111, 112]. ‚ Ë § Ì G1 ¨
S/G2 ¢§ ¨³μ¤¥°¸É¢¨¥ Rad9 ¸ Chk1 ´¥ § ¢¨¸¨É μÉ ¶μ¢·¥¦¤¥´¨° ¨ ±É¨¢´μ¸É¨
CDK1. ‚ G2/M ¢§ ¨³μ¤¥°¸É¢¨¥ ³¥¦¤Ê ´¨³¨ ¶μ²´μ¸ÉÓÕ § ¢¨¸¨É μÉ CAD-Rad9
¨ ±É¨¢´μ¸É¨ CDK1. ‚ G2/M ±¨´ § CDK1 Ëμ¸Ëμ·¨²¨·Ê¥É CAD ¨ ±É¨¢¨·Ê¥É Chk1 Î¥·¥§ ¢§ ¨³μ¤¥°¸É¢¨¥ ¸ CAD-Rad9. ‚ μÉ¢¥É ´ ¶μ¢·¥¦¤¥´¨Ö „Š
CDK1-§ ¢¨¸¨³μ¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ‘-±μ´Í¥¢μ° μ¡² ¸É¨ (’125 ¨ ’143) ¶μ§¢μ²Ö¥É Chk1 ¶¥·¥±²ÕÎ ÉÓ¸Ö ¸ ´¥ ±É¨¢´μ£μ ¢ ±É¨¢´μ¥ ¸μ¸ÉμÖ´¨¥ [113, 114].
‘μ봃 ´¨¥ ´¨§±μ£μ Ê·μ¢´Ö ¸É¨³Ê²¨·ÊÕÐ¥£μ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ’143ph ¨ ¢Ò¸μ±μ£μ Ê·μ¢´Ö ¨´£¨¡¨·ÊÕÐ¥£μ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ’125ph μ£· ´¨Î¨¢ ¥É ¡ §μ¢Ò° ¶Ê² Rad9, ¸¶μ¸μ¡´Ò° ¢§ ¨³μ¤¥°¸É¢μ¢ ÉÓ ¸ Chk1 [115]. μ²ÓÏ Ö Î ¸ÉÓ
Rad9 ´¥ ¸¢Ö§ ´ ¸ Chk1 ¨ ³μ¦¥É μ¡· §μ¢Ò¢ ÉÓ ¤·Ê£¨¥ ±μ³¶²¥±¸Ò, ´¥ ¸μ¤¥·¦ Ш¥ Chk1. Rad9-Chk1 Å ±μ´¸É¨ÉÊɨ¢´Ò°, ´μ ³¨´μ·´Ò° ±μ³¶²¥±¸ Rad9.
Šμ³¶²¥±¸ Rad9-Chk1 ·¥±·Êɨ·Ê¥É¸Ö ¢³¥¸É¥ ¸ ¤·Ê£¨³¨ ±μ³¶²¥±¸ ³¨ Rad9 ±
¸ °ÉÊ ¶μ¢·¥¦¤¥´¨Ö „Š, £¤¥ Rad9 ¶¥·¥Ìμ¤¨É ¨§ ‘- ¢ D-Ëμ·³Ê, ¡¥§μÉ´μ¸¨É¥²Ó´μ ± ¢§ ¨³μ¤¥°¸É¢¨Õ ¸ Chk1. μ¸²¥ ¶μ¢·¥¦¤¥´¨Ö „Š ±¨´ § Chk1
12
¢§ ¨³μ¤¥°¸É¢Ê¥É Éμ²Ó±μ ¸ D-Rad9, ¢ Éμ ¢·¥³Ö ± ± Dpb11 ³μ¦¥É ¢§ ¨³μ¤¥°¸É¢μ¢ ÉÓ ¸ ‘- ¨ D-Ëμ·³ ³¨. ‚Ò¸¢μ¡μ¦¤¥´¨¥ Chk1 μÉ Rad9 ±μ´É·μ²¨·Ê¥É¸Ö
μ¡· ɨ³Ò³ ¸É ÉÊ¸μ³ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ’125 ¨ ’143. „¥Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥
’143 ¨ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ’125, ¶·¥¤¶μ²μ¦¨É¥²Ó´μ, ¤¥¸É ¡¨²¨§¨·ÊÕÉ ¢§ ¨³μ¤¥°¸É¢¨¥ Rad9-Chk1. 줤¥·¦ ´¨¥ ’143ph ¢ μɸÊɸɢ¨¨ ’125ph ¸¶μ¸μ¡¸É¢Ê¥É ¢§ ¨³μ¤¥°¸É¢¨Õ Rad9-Chk1 ¢ ¶·μ±¸¨³ ²Ó´μ° μÉ ¶μ¢·¥¦¤¥´¨Ö μ¡² ¸É¨,
£¤¥ ±¨´ § Chk1 ³μ¦¥É Ëμ¸Ëμ·¨²¨·μ¢ ÉÓ ²μ± ²Ó´Ò¥ ³¨Ï¥´¨.
’ ±¨³ μ¡· §μ³, Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ Rad9 ¶·μ¨¸Ìμ¤¨É ± ± ¶·¨ ¶μ¢·¥¦¤¥´¨¨ „Š, É ± ¨ ¢ μɸÊɸɢ¨¨ ¶μ¢·¥¦¤¥´¨Ö ¢ G2/M, ±μ£¤ ±É¨¢´μ¸ÉÓ
CDK1 ´ ¨¡μ²¥¥ ¢Ò¸μ± . „²Ö ±É¨¢ ͨ¨ Rad9 ¢ G1, ±μ£¤ Rad9 ¨³¥¥É ´¨§±¨° Ê·μ¢¥´Ó CDK1-Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö, ¶·¨μ¡·¥É ¥É ¡μ²¥¥ ¢ ¦´μ¥ §´ Î¥´¨¥
¸É·Ê±ÉÊ· Ì·μ³ É¨´ , Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ 2• ¨ ³¥É¨²¨·μ¢ ´¨¥ 3Š79 [33,
116, 117]. ‚ ¸ °É¥ ¶μ¢·¥¦¤¥´¨Ö „Š ±É¨¢¨·μ¢ ´´ Ö ±¨´ § Œ¥¸1 μ¸ÊÐ¥¸É¢²Ö¥É Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ¨ ·¥³μ¤¥²¨·μ¢ ´¨¥ μ¡μ¨Ì ¡¥²±μ¢ Rad9 [34] ¨
Chk1 [114]. ‚ ·¥§Ê²ÓÉ É¥ ¶·μ¨¸Ìμ¤¨É Í¨¸- ¢ÉμËμ¸Ëμ·¨²¨·μ¢ ´¨¥ Chk1 [118]
¨ ¶μ¸²¥¤ÊÕÐ¥¥ ¢Ò¸¢μ¡μ¦¤¥´¨¥ ¨§ ±μ³¶²¥±¸ D-Rad9-Chk1, ²μ± ²¨§μ¢ ´´μ£μ
´ ¶μ¢·¥¦¤¥´´μ³ Ì·μ³ É¨´¥. ɳ¥É¨³, ÎÉμ ±É¨¢ ꬅ ±¨´ §Ò Chk1 μɲ¨Î ¥É¸Ö μÉ ±É¨¢ ͨ¨ Rad53, ±μÉμ· Ö ¢±²ÕÎ ¥É É· ´¸- ¢ÉμËμ¸Ëμ·¨²¨·μ¢ ´¨¥
¢¸²¥¤ § Œ¥¸1-§ ¢¨¸¨³Ò³ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥³ ¨ ¸¶¥Í¨Ë¨Î¥¸±¨ ¢§ ¨³μ¤¥°¸É¢Ê¥É ¸ Ëμ·³μ° D-Rad9, μ¡· §ÊÕÐ¥°¸Ö ¢ μÉ¢¥É ´ ¶μ¢·¥¦¤¥´¨¥ „Š [36].
±É¨¢´ Ö Rad53 μ¸¢μ¡μ¦¤ ¥É¸Ö μÉ Rad9 ’”-§ ¢¨¸¨³Ò³ ¸¶μ¸μ¡μ³ [35], ±μÉμ·Ò° ´¥ ´ ¡²Õ¤ ¥É¸Ö Ê Chk1.
‘’“Š’“ •Œ’ˆ
‚±² ¤ ±¨´ §Ò CDK1 ¢ ·¥£Ê²ÖÍ¨Õ ±²¥Éμδμ£μ ͨ±² ¶μ¸·¥¤¸É¢μ³ ̨³¨Î¥¸±μ° ³μ¤¨Ë¨± ͨ¨ Ì·μ³μ¸μ³ ³ ²μ ¨§ÊÎ¥´. Š ¸ ³Ò³ ¨§¢¥¸É´Ò³ ¸Ê¡¸É· É ³
±¨´ §Ò μÉ´μ¸¨É¸Ö ²¨´±¥·´Ò° £¨¸Éμ´ 1, ±μÉμ·Ò° ²μ± ²¨§Ê¥É¸Ö ¢ ²¨´±¥·´μ°
„Š ¨ ¸¢Ö§Ò¢ ¥É ¸μ¸¥¤´¨¥ ´Ê±²¥μ¸μ³Ò. ‘ɷʱÉÊ· Ì·μ³ É¨´ Ê ¤·μ¦¦¥° ³¥´¥¥ ±μ´¤¥´¸¨·μ¢ ´´ Ö, ¨ ²¨´±¥·´Ò° ÊÎ ¸Éμ± ±μ·μÎ¥, Î¥³ Ê ³²¥±μ¶¨É ÕШÌ
(165 ¶. ´. ¶·μɨ¢ 205 ¶. ´.). “ ¤·μ¦¦¥° Å μ¤¨´ £¨¸Éμ´ 1, Ê ³²¥±μ¶¨É ÕÐ¨Ì Å 5 ¢ ·¨ ´Éμ¢ 1.
ɲ¨Î ¥É¸Ö ¨ ¸É·Ê±ÉÊ· £¨¸Éμ´ . „·μ¦¦¥¢μ° £¨¸Éμ´ ¨³¥¥É ¤¢ £²μ¡Ê²Ö·´ÒÌ ¤μ³¥´ ¢³¥¸Éμ μ¤´μ£μ. ‚ N-±μ´Í¥¢μ° £²μ¡Ê²¥ · ¸¶μ² £ ÕÉ¸Ö ¸ °ÉÒ ¸¢Ö§Ò¢ ´¨Ö ¸ „Š, ¢ ‘-±μ´Í¥¢μ° Å ¸ °ÉÒ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö. μ± § ´μ, ÎÉμ
¨§ 21 ¶μÉ¥´Í¨ ²Ó´μ£μ ¸ °É Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö 6 ¸ °Éμ¢ Ëμ¸Ëμ·¨²¨·ÊÕɸÖ
±¨´ §μ° CDK1 [119, 120]. “ ³²¥±μ¶¨É ÕÐ¨Ì Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ £¨¸Éμ´ , ¢Ò§Ò¢ ÕÐ¥¥ ¤¥±μ´¤¥´¸ Í¨Õ Ì·μ³ É¨´ , μ¡´ ·Ê¦¥´μ ¢ ¶·μÍ¥¸¸¥ É· ´¸±·¨¶Í¨¨
£¥´μ¢ ¨ ¶·¨ ¨´¨Í¨ ͨ¨ ·¥¶²¨± ͨ¨ [121]. “ ¤·μ¦¦¥° ²¨´±¥·´Ò° £¨¸Éμ´ 1
É ±¦¥ ÊÎ ¸É¢Ê¥É ¢ ·¥£Ê²Öͨ¨ É· ´¸±·¨¶Í¨¨ [122], HR-·¥¶ · ͨ¨ [123], ±É¨¢´μ° ·¥£Ê²Öͨ¨ Ì·μ³ É¨´μ¢μ° ¸É·Ê±ÉÊ·Ò ¢Ò¸μ±μ£μ ¶μ·Ö¤± [124]. ‹¨´±¥·´Ò°
£¨¸Éμ´ ¢§ ¨³μ¤¥°¸É¢Ê¥É ¸ ±μ·μ¢Ò³ £¨¸Éμ´μ³ 4 [122] ¨ ±μ³¶μ´¥´Éμ³ Arp4
13
É·¥Ì ’”-§ ¢¨¸¨³ÒÌ ·¥³μ¤¥²¨·ÊÕÐ¨Ì Ì·μ³ É¨´ ±μ³¶²¥±¸μ¢ INO80, SWR1,
NuA4 [125].
‘ ¤·Ê£μ° ¸Éμ·μ´Ò, ± ¸Ê¡¸É· É ³ ±¨´ §Ò μÉ´μ¸ÖÉ¸Ö ¸Ê¡Ñ¥¤¨´¨ÍÒ ·¥³μ¤¥²¥·μ¢. ¥³μ¤¥²¥·Ò ¶·¨´¨³ ÕÉ ÊÎ ¸É¨¥ ¢ ʧ´ ¢ ´¨¨ ¨ · ¸Î¨¸É±¥ „Š μÉ
´Ê±²¥μ¸μ³ ¢ ¶·μÍ¥¸¸¥ ·¥¶ · ͨ¨. μ± § ´μ, ÎÉμ ¸Ê¡¸É· Éμ³ CDC28 Ö¢²Ö¥É¸Ö
¡¥²μ± Fun30, ¢Ìμ¤ÖШ° ¢ SNF2-¸¥³¥°¸É¢μ ’”-§ ¢¨¸¨³ÒÌ ±μ³¶²¥±¸μ¢ ·¥³μ¤¥²¨´£ Ì·μ³ É¨´ , ±μÉμ·Ò° μÉ¢¥Î ¥É § ¸ °²¥´¸¨´£ ·„Š ¢ Ö¤·¥ [126, 127].
¥£ ɨ¢´Ò° ·¥£Ê²ÖÉμ· Sip2 ±¨´ §Ò Snf1 (¸Ê¡Ñ¥¤¨´¨Í ±μ³¶²¥±¸ SWI/SNF)
É ±¦¥ Ö¢²Ö¥É¸Ö ¸Ê¡¸É· Éμ³ CDC28 [80]. ˆ§¢¥¸É´μ, ÎÉμ ¶·¥¤Ï¥¸É¢ÊÕÐ¥¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ¡¥²± ³μ¦¥É μ¡²¥£Î ÉÓ ¶μ¸²¥¤ÊÕÐÊÕ Ì¨³¨Î¥¸±ÊÕ ³μ¤¨Ë¨± ͨÕ. ’ ±, Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ £¨¸Éμ´ 3 ¶μ Ser10 ±¨´ §μ° Snf1 μ¡²¥£Î ¥É
¤ ²Ó´¥°Ï¥¥ ͥɨ²¨·μ¢ ´¨¥ Lys14 ͥɨ² §μ° Gcn5 (±μ³¶²¥±¸ ·¥³μ¤¥²¨´£ SAGA) [128, 129]. ‚ÒÖ¢²¥´μ £¥´¥É¨Î¥¸±μ¥ ¢§ ¨³μ¤¥°¸É¢¨¥ ³¥¦¤Ê £¥´ ³¨
CDC28 ¨ HFI1 (±μ³¶μ´¥´É ±μ³¶²¥±¸ SAGA), ¤¢μ°´ Ö ³ÊÉ Í¨Ö cdc28-srm
hˇ1-srm ¤ ¥É ¸¨´É¥É¨Î¥¸±ÊÕ ²¥É ²Ó [130]. Š·μ³¥ Éμ£μ, ¸Ê¡¸É· É ³¨ ±¨´ §Ò
CDC28 Ö¢²ÖÕÉ¸Ö ¡¥²±¨ Ngg1 (SAGA) ¨ Spt16 [80]. Spt16 Ö¢²Ö¥É¸Ö É· ´¸±·¨¶Í¨μ´´Ò³ Ë ±Éμ·μ³ Ô²μ´£ ͨ¨ ¨ ¸¢Ö§Ò¢ ¥É¸Ö ¸ ’-±μ³¶²¥±¸μ³ NuA3 [131].
’ ±¨³ μ¡· §μ³, ¢μ¶·μ¸ μ ¢²¨Ö´¨¨ ±¨´ §Ò CDC28 ´ ¸É·Ê±ÉÊ·Ê Ì·μ³ É¨´ § ±μ´μ³¥·¥´ ¨ ´Ê¦¤ ¥É¸Ö ¢ ¤ ²Ó´¥°Ï¥³ ¨§ÊÎ¥´¨¨.
”‡ G1/S
•μÉÖ ±É¨¢ Í¨Ö Î¥±¶μ°´É „ ¢ Ë §¥ G1 ´¥ ´Ê¦¤ ¥É¸Ö ¢ ±¨´ §¥ CDK1,
´ ¡²Õ¤ ¥É¸Ö ¢²¨Ö´¨¥ ³ÊÉ Í¨¨ ± É ²¨É¨Î¥¸±μ° ¸Ê¡Ñ¥¤¨´¨ÍÒ ´ μ¸É ´μ¢±Ê ±²¥Éμδμ£μ ͨ±² ¢ ±Ê²ÓÉÊ· Ì, ¸¨´Ì·μ´¨§μ¢ ´´ÒÌ ¶μ²μ¢Ò³ £μ·³μ´μ³ ¢
Ë §¥ G1 [132]. ’ ±, Ê ³ÊÉ ´Éμ¢ cdc28-srm ´ ¡²Õ¤ ²μ¸Ó ¸´¨¦¥´¨¥ § ¤¥·¦±¨
±²¥Éμδμ£μ ͨ±² ¢ G0 (¸ 50 Ê CDC28 ¤μ 18 ³¨´ Ê cdc28-srm) ¨ G1 (¸ 11
¤μ 0 ³¨´) ¶μ¸²¥ μ¡²ÊÎ¥´¨Ö “”-¸¢¥Éμ³. Š ¸μ¦ ²¥´¨Õ, Ê ³ÊÉ ´É cdc28-srm ´¥
μ¶·¥¤¥²Ö²¨ ±¨´ §´ÊÕ ±É¨¢´μ¸ÉÓ ±μ³¶²¥±¸μ¢ CDK1. “¢¥²¨Î¥´´Ò¥ · §³¥·Ò
±²¥Éμ± Ê± §Ò¢ ÕÉ ´ ¢¥·μÖÉ´Ò¥ ¨§³¥´¥´¨Ö ±¨´ §´μ° ±É¨¢´μ¸É¨, ¸¸μͨ¨·μ¢ ´´μ° ¸ Cln3, ±μÉμ·Ò° μ¶μ¸·¥¤Ê¥É ±μ´É·μ²Ó · §³¥· ±²¥Éμ±. „·Ê£ Ö ³ÊÉ Í¨Ö
cdc28-5M ´¥ Éμ²Ó±μ ¢²¨Ö² ´ μ¸É ´μ¢±Ê, ¢Ò§¢ ´´ÊÕ “”-¶μ¢·¥¦¤¥´¨Ö³¨, ´μ
É ±¦¥ ¸´¨¦ ² ±¨´ §´ÊÕ ±É¨¢´μ¸ÉÓ, ¸¸μͨ¨·μ¢ ´´ÊÕ ¸ ͨ±²¨´ ³¨ Clb5 ¨
Clb6 [133]. “ ³ÊÉ ´É´ÒÌ ±²¥Éμ± cdc28-as1, Ê ±μÉμ·ÒÌ ¨´ ±É¨¢ Í¨Õ ±¨´ §´μ°
±É¨¢´μ¸É¨ μ¸ÊÐ¥¸É¢²Ö²¨ ’”- ´ ²μ£μ³ 1-NM-PP1, ¶μ¸²¥ ¨´¤Ê±Í¨¨ „ ¸
¶μ³μÐÓÕ -Ô´¤μ´Ê±²¥ §Ò ¢ G1 ´¥ ´ ¡²Õ¤ ²¨ ±É¨¢ Í¨Õ Î¥±¶μ°´É [83].
¡²Õ¤ ¥³ Ö · §´¨Í , ¢μ§³μ¦´μ, ¸¢Ö§ ´ ¸ · §²¨Î´μ° ¶·¨·μ¤μ° ¶μ¢·¥¦¤¥´¨° „Š.
Œμ¦´μ ¶·¥¤¶μ²μ¦¨ÉÓ, ÎÉμ ´ · ´´¨Ì ¸É ¤¨ÖÌ ±²¥Éμδμ£μ ͨ±² ¶μ¢·¥¦¤¥´¨Ö „Š ³μ£ÊÉ § ³¥¤²ÖÉÓ ¢¸Éʶ²¥´¨¥ ¢ Ë §Ê S § ¸Î¥É ¨´£¨¡¨·μ¢ ´¨Ö
Ëμ·³Ò ±¨´ §Ò CDK1, ´¥μ¡Ì줨³μ° ¤²Ö ¶·μÌ즤¥´¨Ö ‘É ·É . G1 Î¥±¶μ°´É
³μ¦¥É ±μ´É·μ²¨·μ¢ ÉÓ ±É¨¢´μ¸ÉÓ ´¥±μÉμ·ÒÌ ±¨´ §´ÒÌ ±μ³¶²¥±¸μ¢ ¶μ¸·¥¤14
¸É¢μ³ ·¥£Ê²Öͨ¨ É· ´¸±·¨¶Í¨¨ G1-ͨ±²¨´μ¢. „¥°¸É¢¨É¥²Ó´μ, G1-ͨ±²¨´Ò, ¢
´μ·³¥ ´¥μ¡Ì줨³Ò¥ ¤²Ö ¶¥·¥Ìμ¤ G1/S, ¨´ ±É¨¢¨·ÊÕÉ¸Ö ¶μ¸²¥ ¶μ¢·¥¦¤¥´¨Ö
³μ²¥±Ê² „Š. μ± § ´μ, ÎÉμ ¶μ¢·¥¦¤¥´¨Ö „Š ±É¨¢¨·ÊÕÉ Î¥±¶μ°´É´ÊÕ
±¨´ §Ê Rad53, ±μÉμ· Ö Ëμ¸Ëμ·¨²¨·Ê¥É ¨ É¥³ ¸ ³Ò³ ¨´ ±É¨¢¨·Ê¥É Swi6, ±μ ±É¨¢ Éμ· É· ´¸±·¨¶Í¨¨ G1-ͨ±²¨´μ¢ CLN1 ¨ CLN2 [134, 135]. ƒ¨¶¥·Ô±¸¶·¥¸¸¨Ö ͨ±²¨´μ¢ ¨²¨ ³ÊÉ Í¨¨ ± É ²¨É¨Î¥¸±μ° ¸Ê¡Ñ¥¤¨´¨ÍÒ, ¶μ¢ÒÏ ÕШ¥
˨´´μ¸ÉÓ ± G1-ͨ±²¨´ ³, ¨´ ±É¨¢¨·ÊÕÉ Î¥±¶μ°´É ¢ G1. Œ„-¸¨³Ê²¨·μ¢ ´¨¥
¸É·Ê±ÉÊ·Ò ³ÊÉ ´É´μ° Ëμ·³Ò ±¨´ §Ò ‘dc28-srm ¢ÒÖ¢¨²μ ¸³¥Ð¥´¨¥ ¶¥É²¨
PSTAIRE ± ± ¢μ§³μ¦´ÊÕ ¶·¨Î¨´Ê ³μ¤¨Ë¨± ͨ¨ ¢§ ¨³μ¤¥°¸É¢¨Ö ¸ ͨ±²¨´ ³¨ [136]. ‚ Ë §¥ G1 ±¨´ § CDK1 ¢Ò¸Éʶ ¥É £² ¢´Ò³ μ¡· §μ³ ¢ ± Î¥¸É¢¥
ÔËË¥±Éμ· Î¥±¶μ°´É-·¥£Ê²Öͨ¨.
”‡ S
—¥±¶μ°´É-§ ¢¨¸¨³ÊÕ μ¸É ´μ¢±Ê ¤¥²¥´¨Ö ±²¥É±¨ ¢ Ë §¥ S ¢Ò§Ò¢ ¥É ƒŒ,
¶μ¤ ¢²ÖÕÐ Ö ·¥¶²¨± Í¨Õ „Š ¢ ·¥§Ê²ÓÉ É¥ ¨¸ÉμÐ¥´¨Ö ¶Ê² ¶·¥¤Ï¥¸É¢¥´´¨±μ¢ ´Ê±²¥μɨ¤μ¢, ¶·¥¨³ÊÐ¥¸É¢¥´´μ ¢ ·¥§Ê²ÓÉ É¥ ¨´£¨¡¨·μ¢ ´¨Ö ·¨¡μ´Ê±²¥μɨ¤·¥¤Ê±É §Ò () [137]. ‚ ²¨É¥· ÉÊ·¥ ¤ ´´Ò¥ μ¡ ÊÎ ¸É¨¨ CDC28 ¢ S
Î¥±¶μ°´É¥ μɸÊɸɢÊÕÉ. ·Ö³μ¥ ¨§ÊÎ¥´¨¥ ËÊ´±Í¨μ´¨·μ¢ ´¨Ö ±¨´ §Ò ¶μ± § ²μ, ÎÉμ CDC28 ´¥ ¢²¨Ö¥É ´ ±É¨¢ Í¨Õ Î¥±¶μ°´É ¢ Ë §¥ S. ‘¨´Ì·μ´¨§ ͨÖ
cdc28-as1 ±²¥Éμ± ¢ Ë §¥ S ´¥ ¶·¨¢¥² ± ¶μ¢ÒÏ¥´¨Õ ÎÊ¢¸É¢¨É¥²Ó´μ¸É¨ ± ²¥É ²Ó´μ³Ê ¤¥°¸É¢¨Õ ƒŒ ¨²¨ ³¥É¨²³¥É ´¸Ê²ÓËμ´ É (ŒŒ‘) ¨ ´¥ ¶μ¢²¨Ö² ´ μ¡· §μ¢ ´¨¥ Ddc2-Í¥´É·μ¢ [138]. Éμ ¸μ£² ¸Ê¥É¸Ö ¸ ¶·¥¤¸É ¢²¥´¨¥³, ÎÉμ ±¨´ § CDC28 ¸ ³ ¶μ ¸¥¡¥ ´¥ Ö¢²Ö¥É¸Ö ¸ÊÐ¥¸É¢¥´´μ° ¤²Ö ±É¨¢ ͨ¨ Rad53
¢ ÔÉμ° Ë §¥ ±²¥Éμδμ£μ ͨ±² [92]. ¤´ ±μ ÌμÉÖ ´ Î ¸ÉμÉÊ μ¡· §μ¢ ´¨Ö
Ddc2-Ëμ±Ê¸μ¢ ±É¨¢´μ¸ÉÓ CDC28 ´¥ ¢²¨Ö² , ¨´É¥´¸¨¢´μ¸ÉÓ Ddc2-Ëμ±Ê¸μ¢
¡Ò² ´¨¦¥ ¢ ±²¥É± Ì cdc28-as1 ¢ ¶·¨¸Êɸɢ¨¨ 1-NP-PP1. Š·μ³¥ Éμ£μ, μÉ
CDC28 § ¢¨¸¥² ±É¨¢ ꬅ Rad53 “”-³¨³¥É¨±μ³ 4-´¨É·μ̨´μ²¨´-1-μ±¸¨¤μ³
(4-NQO) [83] ¨ ŒŒ‘ [138]. ”μ¸Ëμ·¨²¨·μ¢ ´¨¥ Rad53, ¨´¤Êͨ·μ¢ ´´μ¥
˲¥μ³¨Í¨´μ³, ¡Ò²μ Î ¸É¨Î´μ ¸´¨¦¥´μ Ê ±²¥Éμ± ³ÊÉ ´É cdc28-as1, μ¡· ¡μÉ ´´ÒÌ 1-NP-PP1 [138]. μ-¢¨¤¨³μ³Ê, ±É¨¢ Í¨Ö Î¥±¶μ°´É ¶μ¢·¥¦¤¥´¨Ö³¨
„Š, ¨´¤Êͨ·μ¢ ´´Ò³¨ ˲¥μ³¨Í¨´μ³, Î ¸É¨Î´μ § ¢¨¸¨É μÉ CDC28.
ŒÊÉ Í¨¨ cdc28-srm [132], cdc28-5M [133] ¨ cdc28-Y19F ¨²¨ ¨´£¨¡¨·μ¢ ´¨¥ ±¨´ §´μ° ±É¨¢´μ¸É¨ [139] É ±¦¥ ´¥ ¢²¨ÖÕÉ ´ S Î¥±¶μ°´É, ´μ
´ ¡²Õ¤ ²μ¸Ó ´¥¡μ²ÓÏμ¥ ¢²¨Ö´¨¥ ³ÊÉ Í¨° cdc28-srm, cdc28-5M ¨ cdc28-as1
´ ÎÊ¢¸É¢¨É¥²Ó´μ¸ÉÓ ± ƒŒ [132, 138]. ŒÊÉ Í¨Ö cdc28-srm ¢²¨Ö¥É É ±¦¥ ´ Î¥±¶μ°´É-§ ¢¨¸¨³ÊÕ μ¸É ´μ¢±Ê ¤¥²¥´¨Ö ¢ ¶μ§¤´¥° S/G2 ¨ ¢ G2 Ë § Ì Ê ·¥¶²¨± ɨ¢´ÒÌ ³ÊÉ ´Éμ¢ cdc6-1 ¨ cdc9-1 ¸μμÉ¢¥É¸É¢¥´´μ [132]. ‚μ§³μ¦´μ, ÎÉμ
¢²¨Ö´¨¥ CDC28 ´ Î¥±¶μ°´É ¢ Ë §¥ S ¶μ± ´¥¤μ¸É ÉμÎ´μ ¨§ÊÎ¥´μ.
„²¨É¥²Ó´ Ö μ¸É ´μ¢± ·¥¶²¨± ɨ¢´μ° ¢¨²±¨ ³μ¦¥É ¶·¨¢μ¤¨ÉÓ ± ±μ²² ¶¸Ê
¨ ¢μ§´¨±´μ¢¥´¨Õ „. μ¸²¥ μ¡· ¡μɱ¨ ƒŒ Î ¸ÉÓ ±²¥Éμ± cdc28-5M ¸μ¤¥·15
¦¨É Ë· ±Í¨Õ ¸Ê¡-G1-„Š, ÎÉμ ¸¢¨¤¥É¥²Ó¸É¢Ê¥É μ ³¨ÉμɨΥ¸±μ° ± É ¸É·μË¥
¨ ¸μ£² ¸Ê¥É¸Ö ¸ ¶·¥¤¶μ²μ¦¥´¨¥³ μ¡ ÊÎ ¸É¨¨ CDC28 ¢ ¶·¥¤μÉ¢· Ð¥´¨¨ ³¨ÉμɨΥ¸±μ° ± É ¸É·μËÒ [140].
짤´¨¥ ori. ‚±²ÕÎ¥´¨¥ ori-·¥¶²¨± ͨ¨ ¨´£¨¡¨·Ê¥É¸Ö ¢ ¶·μÍ¥¸¸¥ Ë §Ò S,
¥¸²¨ ¶μ¢·¥¦¤¥´¨Ö „Š ¨²¨ § ¸É·Ö¢Ï Ö ·¥¶²¨± ɨ¢´ Ö ¢¨²± ±É¨¢¨·ÊÕÉ
Î¥±¶μ°´É-±¨´ §Ò.
Rad53 ¶μ¤ ¢²Ö¥É ±É¨¢ Í¨Õ ¶μ§¤´¨Ì ori-·¥¶²¨± ͨ¨ [141, 142] ´ ¸É ¤¨¨ ¶μ¸²¥ μ¡· §μ¢ ´¨Ö ¶·¥·¥¶²¨± ɨ¢´μ£μ ±μ³¶²¥±¸ (¶·¥-Š), ´μ ¤μ μ¡· §μ¢ ´¨Ö ¶·¥¨´¨Í¨¨·ÊÕÐ¥£μ ±μ³¶²¥±¸ (¶·¥-ˆŠ) [7].
—¥±¶μ°´É-±¨´ § Rad53, É ± ¦¥ ± ± ¨ ¢ Ë §¥ G1, ¨´£¨¡¨·Ê¥É μ¡ CDK1¨ DDK-§ ¢¨¸¨³Ò¥ ±¨´ §´Ò¥ ¶Êɨ, ±μÉμ·Ò¥ ¸ ¨§¡ÒÉ±μ³ ¡²μ±¨·ÊÕÉ ¤ ²Ó´¥°Ï¥¥ ¢±²ÕÎ¥´¨¥ ori [142]. Rad53 ¤¥°¸É¢Ê¥É ´ DDK ´ ¶·Ö³ÊÕ, ˨§¨Î¥¸±¨
¢§ ¨³μ¤¥°¸É¢ÊÖ ¨ Ëμ¸Ëμ·¨²¨·ÊÖ ¥¥ ¸Ê¡Ñ¥¤¨´¨ÍÊ Dbf4 (ƒŒ-¨´¤Êͨ·μ¢ ´´μ¥
£¨¶¥·Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ Dbf4 § ¢¨¸¨É μÉ Rad53 ¨ Mec1), ÎÉμ ¸¶μ¸μ¡¸É¢Ê¥É
¨´£¨¡¨·μ¢ ´¨Õ ±¨´ §Ò DDK ¨ ʤ ²¥´¨Õ ¥¥ ¨§ Ì·μ³ É¨´ [143Ä146]. ‚ Éμ ¦¥
¢·¥³Ö CDK1-¶ÊÉÓ ¡²μ±¨·Ê¥É¸Ö Rad53-μ¶μ¸·¥¤μ¢ ´´Ò³ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥³
¸Ê¡¸É· É CDK1, Sld3. Éμ ¶μ§¢μ²Ö¥É CDK1 ¢ ¶·¨¸Êɸɢ¨¨ ¶μ¢·¥¦¤¥´¨Ö
„Š ¸μÌ· ´ÖÉÓ ±É¨¢´μ¸ÉÓ ¢ Ë §¥ S, ±μÉμ· Ö ±·¨É¨Î´ ¤²Ö ¶·¥¤μÉ¢· Ð¥´¨Ö
¶μ¢Éμ·´μ° § £·Ê§±¨ Mcm2-7 ´ ʦ¥ μɱ·ÒÉÒ¥ ori-·¥¶²¨± ͨ¨. ’ ±¨³ μ¡· §μ³, § ³¥¤²¥´¨¥ Ë §Ò S ¢ ¸²ÊÎ ¥ intra-S Î¥±¶μ°´É ¶·¥¦¤¥ ¢¸¥£μ μ¡Ê¸²μ¢²¥´μ
¶μ¤ ¢²¥´¨¥³ ±É¨¢ ͨ¨ ori-·¥¶²¨± ͨ¨ (¸³. ·¨¸Ê´μ±).
’¥²μ³¥·Ò. ˆ´ ±É¨¢ ꬅ ±Ô¶-±μ³¶²¥±¸ ¢Ò§Ò¢ ¥É μ£μ²¥´¨¥ É¥²μ³¥·Ò,
¸μ¶·μ¢μ¦¤ ÕÐ¥¥¸Ö ¤¥£· ¤ ͨ¥° É¥²μ³¥·´μ° „Š. ±μ¶²¥´¨¥ μ´„Š ¸¢¥·Ì
¶μ·μ£μ¢μ£μ §´ Î¥´¨Ö ¢Ò§Ò¢ ¥É μÉ¢¥É ±²¥É±¨ ´ ¶μ¢·¥¦¤¥´¨Ö „Š ¨ μ¸É ´μ¢±Ê
ͨ±² ¤¥²¥´¨Ö ¢ G2/M [8, 9, 147].
Šμ³¶²¥±¸ CST (Cdc13-Stn1-Ten1) Ö¢²Ö¥É¸Ö Ô¢μ²ÕÍ¨μ´´μ ±μ´¸¥·¢ ɨ¢´Ò³ RPA-¶μ¤μ¡´Ò³ ±μ³¶²¥±¸μ³, ¸¢Ö§Ò¢ ÕШ³¸Ö ¸ É¥²μ³¥·´Ò³ 3 -Ì¢μ¸Éμ³
μ´„Š [8, 148, 149]. μ² £ ÕÉ, ÎÉμ CST ¶·¥¤μÉ¢· Ð ¥É ¶·μÍ¥¸¸¨´£ É¥²μ³¥·´μ° μ´„Š, ¶μ¤μ¡´μ RPA ¢ ¸²ÊÎ ¥ „ [150]. Cdc13 ¸¢Ö§Ò¢ ¥É¸Ö ¸
G-¡μ£ Éμ° μ´„Š ¨ § ШР¥É ¶·μɨ¢μ¶μ²μ¦´ÊÕ ‘-¡μ£ ÉÊÕ Í¥¶Ó μÉ ¤¥£· ¤ ͨ¨. ²²¥²Ó cdc13-1 ts ¶μ§¢μ²Ö¥É ¨§ÊÎ ÉÓ ¶μ¢¥¤¥´¨¥ ´¥±Ô¶¨·μ¢ ´´ÒÌ É¥²μ³¥·
¢ · §²¨Î´Ò¥ ³μ³¥´ÉÒ ±²¥Éμδμ£μ ͨ±² , É ±¦¥ ¸É¥¶¥´Ó ¤¥£· ¤ ͨ¨ É¥²μ³¥·
¨ ¦¨§´¥¸¶μ¸μ¡´μ¸ÉÓ ±²¥Éμ±. ± § ²μ¸Ó, ÎÉμ ´¥±Ô¶¨·μ¢ ´´Ò¥ ±μ´ÍÒ Ì·μ³μ¸μ³
¸É ¡¨²Ó´Ò ¢ G1- ·¥¸Éμ¢ ´´ÒÌ ±²¥É± Ì, ¶·¨Î¥³ ±²¥É±¨ ¸μÌ· ´Ö²¨ ¢Ò¸μ±ÊÕ
¦¨§´¥¸¶μ¸μ¡´μ¸ÉÓ [147]. ¤´ ±μ ¢ ±²¥É± Ì, ·¥¸Éμ¢ ´´ÒÌ ¢ G2/M, É¥²μ³¥·´ Ö „Š ¶μ¤¢¥·£ ² ¸Ó ¨´É¥´¸¨¢´μ° ¤¥£· ¤ ͨ¨, ¨ ±²¥É±¨ ¸μ ¢·¥³¥´¥³ £¨¡²¨.
’ ±¨³ μ¡· §μ³, μɸÊɸɢ¨¥ · ¸Ð¥¶²¥´¨Ö ‘-±μ´Í É¥²μ³¥· ¢ G1 ¨³¥¥É ¸Ìμ¤¸É¢μ ¸μ ¸É ¡¨²Ó´μ¸ÉÓÕ ¨´¤Êͨ·μ¢ ´´ÒÌ -Ô´¤μ´Ê±²¥ §μ° ±μ´Íμ¢ „ ¢ G1 ·¥¸Éμ¢ ´´ÒÌ ±²¥É± Ì [151] ¨ ¸ ´¥¸¶μ¸μ¡´μ¸ÉÓÕ ¶·μÍ¥¸¸¨·μ¢ ÉÓ É ±¨¥ „,
μ¡Ê¸²μ¢²¥´´μ° μɸÊɸɢ¨¥³ ±É¨¢´μ¸É¨ Cdc28/Clb ¢ ÔÉμÉ ³μ³¥´É [83, 152].
’ ±¨³ μ¡· §μ³, ¶·μÍ¥¸¸¨´£ ± ± ´¥ËÊ´±Í¨μ´ ²Ó´ÒÌ É¥²μ³¥·, É ± ¨ ¸²ÊÎ °´ÒÌ „ ±É¨¢´μ¸ÉÖ³¨ ·¥¶ · ͨ¨ „Š ·¥£Ê²¨·Ê¥É¸Ö ¸¶μ¸μ¡μ³, § ¢¨¸ÖШ³
μÉ ±²¥Éμδμ£μ ͨ±² ¨ CDK1 (Cdc28/Clb). Cdc13 Ö¢²Ö¥É¸Ö ¸Ê¡¸É· Éμ³ ±¨´ §Ò
16
CDK1 [7]. £μ²¥´´Ò¥ É¥²μ³¥·Ò ʧ´ ÕÉ¸Ö ±μ³¶²¥±¸μ³ Ddc1-Mec3-Rad17.
‚ ¤¥£· ¤ ͨ¨ ´¥±Ô¶¨·μ¢ ´´ÒÌ É¥²μ³¥· ÊÎ ¸É¢ÊÕÉ Exo1 ¨ Sgs1, É ±¦¥ ¤·Ê£¨¥ ´Ê±²¥ §Ò. ‚ · ¸Ð¥¶²¥´¨¨ ´¥§ ШХ´´ÒÌ É¥²μ³¥·, ´μ ´¥ ±μ´Íμ¢ „,
ÊÎ ¸É¢Ê¥É 5 -3 -£¥²¨± § Pif1. ‚ ±²¥É± Ì ¶μαÊÕÐ¨Ì¸Ö ¤·μ¦¦¥° ±μ³¶²¥±¸
CST ¨£· ¥É ¤¢μ°´ÊÕ ·μ²Ó Å ¨´£¨¡¨·μ¢ ´¨¥ μÉ¢¥É ´ ¶μ¢·¥¦¤¥´¨Ö „Š,
± ± ¸¸μͨ¨·μ¢ ´´μ£μ ¸ „ ¨ ±É¨¢¨·Ê¥³μ£μ Exo1, É ± ¨ ¸¸μͨ¨·μ¢ ´´μ£μ
¸ ·¥¶²¨± ͨ¥° ¨ ¨´¨Í¨¨·Ê¥³μ£μ £¥²¨± §μ° Pif1 [153]. ˆ´Ò³¨ ¸²μ¢ ³¨, μÉ¢¥É ´ ´¥§ ШХ´´ÒÌ É¥²μ³¥· Ì Î ¸É¨Î´μ μ¡Ê¸²μ¢²¥´ ¸Ìμ¤¸É¢μ³ ¸ „, ¸
¤·Ê£μ° ¸Éμ·μ´Ò Å ¤¥Ë¥±Éμ³ ·¥¶²¨± ͨ¨ „Š.
‚ ·¥§Ê²ÓÉ É¥ ¤¥£· ¤ ͨ¨ μ¡· §Ê¥É¸Ö ¶·μÉÖ¦¥´´Ò° É·Ô± μ´„Š, ±μÉμ·Ò°
¢Ò§Ò¢ ¥É ÊÉ· ÉÊ ¦¨§´¥¸¶μ¸μ¡´μ¸É¨ ¨ ¸É¨³Ê²¨·Ê¥É Œ¥¸1-§ ¢¨¸¨³ÊÕ ±É¨¢ Í¨Õ Î¥±¶μ°´É ¨ ·¥¸É ±²¥Éμδμ£μ ͨ±² , ´ ²μ£¨Î´μ μÉ¢¥ÉÊ ´ „ [8, 154,
155]. MRX ¶μ¤ ¢²Ö¥É ¤¥£· ¤ ͨÕ, ¶·¨¢²¥± Ö ¶·μÉ¥±Éμ·´Ò¥ É¥²μ³¥·´Ò¥ ¡¥²±¨
(É¥²μ³¥· § ). „¥£· ¤ ꬅ ´Ê±²¥ §μ° Sae2, ¶μ-¢¨¤¨³μ³Ê, ¸É¨³Ê²¨·Ê¥É ´Ê±²¥ §´ÊÕ ±É¨¢´μ¸ÉÓ Mre11. ‚ ·¥§Ê²ÓÉ É¥ ¨´Í¨§¨¨ 3 -´¨É¨ ¶·μ¨¸Ìμ¤ÖÉ ¢Ò¸¢μ¡μ¦¤¥´¨¥ ±μ³¶²¥±¸ MRX μÉ „ ¨ ±É¨¢ ꬅ Œ¥¸1-§ ¢¨¸¨³μ£μ μÉ¢¥É [92].
ˆ, ´ μ¡μ·μÉ, ¢ μɸÊɸɢ¨¨ ¤¥£· ¤ ͨ¨ ±μ³¶²¥±¸ MRX ¸μÌ· ´Ö¥É ¸É ¡¨²Ó´ÊÕ
¸¢Ö§Ó ¸ „ ¨ ¸²Ê¦¨É ¸É¨³Ê²μ³ ¤²Ö ±É¨¢ ͨ¨ Î¥±¶μ°´É ±¨´ §μ° Tel1 Î¥·¥§
¸¢μÕ ¸Ê¡Ñ¥¤¨´¨ÍÊ Xrs2 [156, 157]. ‡ É¥³ Tel1 ´ ²μ£¨Î´μ Œ¥¸1 ±É¨¢¨·Ê¥É
Î¥±¶μ°´É, ·¥±·Êɨ·ÊÖ ³¥¤¨ Éμ· Rad9 ¨ ±É¨¢¨·ÊÖ ¶μ¸²¥¤ÊÕШ° ±¨´ §´Ò°
± ¸± ¤ [157]. Tel1, ¶μ-¢¨¤¨³μ³Ê, ¨³¥¥É ¤μ¶μ²´¨É¥²Ó´ÊÕ ·μ²Ó ¢ ¤¥£· ¤ ͨ¨ „ [48].
…ƒ“‹Ÿ–ˆŸ ’‘Šˆ–ˆˆ
·μ£· ³³ É· ´¸±·¨¶Í¨¨ ¢ ¶·μÍ¥¸¸¥ ±²¥Éμδμ£μ ͨ±² μ¶·¥¤¥²Ö¥É ¶μ·Ö¤μ± ¸μ¡Òɨ° ±²¥Éμδμ£μ ͨ±² ¨ Ö¢²Ö¥É¸Ö ³¨Ï¥´ÓÕ ¸¨£´ ²μ¢, ·¥£Ê²¨·ÊÕШÌ
¶·μÌ즤¥´¨¥ ±²¥Éμδμ£μ ͨ±² , ¢ Éμ³ Î¨¸²¥ Î¥±¶μ°´É-·¥£Ê²ÖͨÕ. —¥±¶μ°´ÉμÉ¢¥É ¢±²ÕÎ ¥É ¢ ¸¥¡Ö ¨´¤Ê±Í¨Õ É· ´¸±·¨¶Í¨¨ £¥´μ¢, μ¸ÊÐ¥¸É¢²ÖÕÐ¨Ì ¸É ¡¨²¨§ Í¨Õ ·¥¶²¨± ɨ¢´μ° ¢¨²±¨ ¢ ¸²ÊÎ ¥ ´ ·ÊÏ¥´¨Ö ·¥¶²¨± ͨ¨ ¨²¨ ·¥¶ · ͨÕ. ’· ´¸±·¨¶Í¨μ´´Ò° μÉ¢¥É μ¸ÊÐ¥¸É¢²ÖÕÉ ±¨´ §Ò Mec1, Rad53 ¨
Ëμ¸Ëμ·¨²¨·Ê¥³ Ö ¥Õ ±¨´ § Dun1.
±¸¶·¥¸¸¨Ö G1/S £¥´μ¢ ·¥£Ê²¨·Ê¥É¸Ö ¤¢Ê³Ö É· ´¸±·¨¶Í¨μ´´Ò³¨ Ë ±Éμ· ³¨ Å SBF ¨ MBF, ¨³¥ÕШ³¨ μ¤´Ê μ¡ÐÊÕ ¸Ê¡Ñ¥¤¨´¨ÍÊ Swi6 ¨, ¸μμÉ¢¥É¸É¢¥´´μ, ¤¢ ¡¥²± Swi4 ¨ Mbp1, ¸¢Ö§Ò¢ ÕÐ¨Ì¸Ö ¸μ ¸¶¥Í¨Ë¨Î¥¸±¨³¨ ¶μ¸²¥¤μ¢ É¥²Ó´μ¸ÉÖ³¨ „Š. SBF ËÊ´±Í¨μ´¨·Ê¥É ¢ μ¸´μ¢´μ³ ± ± É· ´¸±·¨¶Í¨μ´´Ò° ±É¨¢ Éμ· ¢ G1, MBF μ¸ÊÐ¥¸É¢²Ö¥É ·¥£Ê²ÖÍ¨Õ É· ´¸±·¨¶Í¨¨ ¶·¨
¶¥·¥Ì줥 G1/S. ·¨Î¥³ £¥´Ò, ÊÎ ¸É¢ÊÕШ¥ ¢ ¸¢μ¥¢·¥³¥´´μ¸É¨ ¨ ÔËË¥±É¨¢´μ¸É¨ ¸μ¡Òɨ° ´ Î ² ±²¥Éμδμ£μ ͨ±² , ·¥£Ê²¨·ÊÕɸÖ, £² ¢´Ò³ μ¡· §μ³, SBF,
¢ Éμ ¢·¥³Ö ± ± £¥´Ò, ÊÎ ¸É¢ÊÕШ¥ ¢ ¨´¨Í¨ ͨ¨ ·¥¶²¨± ͨ¨ „Š ¨ ¸¨´É¥§¥
´Ê±²¥μɨ¤μ¢, ΠХ ±μ´É·μ²¨·ÊÕÉ¸Ö Ë ±Éμ·μ³ MBF.
17
‚ · ´´¥° Ë §¥ S ±¨´ §Ò Cdc28/Cln1 ¨ Cdc28/Cln2 ±É¨¢¨·ÊÕÉ MBF
(Swi6/Mbp1), Ë ±Éμ· É· ´¸±·¨¶Í¨¨ ͨ±²¨´μ¢ Clb5 ¨ Clb6 ¨ ¤·Ê£¨Ì £¥´μ¢
·¥¶²¨± ͨ¨ „Š. –¨±²¨´Ò Clb5 ¨ Clb6 ÊÎ ¸É¢ÊÕÉ ¢ ¸¡μ·±¥ ¶·¥-ˆŠ, ±É¨¢¨·ÊÖ CDK1/Clb-§ ¢¨¸¨³μ¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ¡¥²±μ¢ Sld2 ¨ Sld3 [7]. ’ ±
± ± S-CDK ʶ· ¢²ÖÕÉ ¢¸Éʶ²¥´¨¥³ ¨ ¶·μÌ즤¥´¨¥³ Ë §Ò S, μ´¨ Ö¢²ÖÕɸÖ
¶·¨¢²¥± É¥²Ó´Ò³¨ ³¨Ï¥´Ö³¨ Î¥±¶μ°´É . „¥°¸É¢¨É¥²Ó´μ, ¡Ò²μ ¶μ± § ´μ, ÎÉμ
S-ͨ±²¨´Ò Clb5 ¨ Clb6 ·¥£Ê²¨·ÊÕÉ¸Ö ¢ μÉ¢¥É ´ £¥´μÉμ±¸¨Î¥¸±¨° ¸É·¥¸¸ [158].
¥¸É ¡¨²Ó´Ò° Clb6, · ´μ Ô²¨³¨´¨·ÊÕШ°¸Ö ¢ ʸ²μ¢¨ÖÌ ´¥¢μ§³ÊÐ¥´´μ°
Ë §Ò S, ¸É ¡¨²¨§¨·Ê¥É¸Ö ¢ μÉ¢¥É ´ £¥´μÉμ±¸¨Î¥¸±¨° ¸É·¥¸¸. „²Ö ¸É ¡¨²¨§ ͨ¨ ´¥μ¡Ì줨³ ±¨´ § Rad53 (´μ ´¥ ±¨´ § Dun1), É· ´¸±·¨¶Í¨μ´´Ò°
Ë ±Éμ· MBF ¨ ±É¨¢´Ò° ¸¨´É¥§ ¡¥²± de novo. Swi6, É· ´¸ ±É¨¢ Í¨μ´´ Ö ¸Ê¡Ñ¥¤¨´¨Í MBF, ¸μÌ· ´Ö¥É Ö¤¥·´ÊÕ ²μ± ²¨§ Í¨Õ ¢ ±²¥É±¥ ¢ ʸ²μ¢¨ÖÌ
£¥´μÉμ±¸¨Î¥¸±μ£μ ¸É·¥¸¸ , ´¥¸³μÉ·Ö ´ ´ ²¨Î¨¥ Clb6. CDK1/Clb6, ´μ ´¥
CDK1/Clb5, μ¶μ¸·¥¤Ê¥É ¢Ò¢¥¤¥´¨¥ Swi6 ¨§ Ö¤· ¢ ´¥¢μ§³ÊÐ¥´´μ° Ë §¥ S ± ±
Î ¸ÉÓ ·¥£Ê²ÖÉμ·´μ£μ ±μ´É·μ²Ö ±É¨¢´μ¸É¨ MBF [159]. ¤´ ±μ S Î¥±¶μ°´É
μɳ¥´Ö¥É É ±μ° ±μ´É·μ²Ó. ˆ§¢¥¸É´μ, ÎÉμ Rad53 Ëμ¸Ëμ·¨²¨·Ê¥É Swi6 [135],
Clb6 É ±¦¥ Ö¢²Ö¥É¸Ö ¸Ê¡¸É· Éμ³ Rad53 in vitro. ‚¶μ²´¥ ¢¥·μÖÉ´μ, ÎÉμ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ±¨´ §μ° Rad53 É ±¨Ì ¸Ê¡¸É· Éμ¢, ± ± Swi6 ¨ Clb6, ´ ·ÊÏ ¥É
¨Ì ˨´´μ¸ÉÓ, ¤¥² Ö ¢μ§³μ¦´Ò³ Ö¤¥·´ÊÕ ²μ± ²¨§ Í¨Õ Swi6.
‚ ±²¥É± Ì μ¡´ ·Ê¦¨¢ ÕÉ¸Ö ¤¢¥ Ëμ·³Ò Í¨±²¨´ Clb5. “¸Éμ°Î¨¢Ò° Ê·μ¢¥´Ó Clb5 ¢ ´¥¢μ§³ÊÐ¥´´μ° Ë §¥ S μ¡¥¸¶¥Î¨¢ ¥É¸Ö ¡ ² ´¸μ³ ³¥¦¤Ê ¶·μ¤μ²¦ ÕШ³¸Ö ¸¨´É¥§μ³ ¨ ¤¥£· ¤ ͨ¥° ´¥¸É ¡¨²Ó´μ° Ëμ·³Ò ¡¥²± . ‚ ¶·μɨ¢μ¶μ²μ¦´μ¸ÉÓ ¨¸ÉμÐ¥´¨Õ CLB6-³Š ¢ Ë §¥ S, CLB5-³Š ¶·μ¤μ²¦ ¥É ¶·¨¸ÊÉ¸É¢μ¢ ÉÓ, μ¡¥¸¶¥Î¨¢ Ö ´¥μ¡Ì줨³Ò¥ ³ É·¨ÍÒ ¤²Ö ¶·μ¤μ²¦ ÕÐ¥£μ¸Ö ¸¨´É¥§ ¡¥²± . μ²¥¥ Éμ£μ, ¢ ¶·μɨ¢μ¶μ²μ¦´μ¸ÉÓ Clb6 Ê·μ¢¥´Ó Clb5 μ¸É ¥É¸Ö ¶μ¸ÉμÖ´´Ò³ ¤ ¦¥ ¢ ʸ²μ¢¨ÖÌ ¡²μ± ¡¥²±μ¢μ£μ ¸¨´É¥§ ¨²¨ ¶·¨ ¸¢¥·ÌÔ±¸¶·¥¸¸¨¨ £¨¶¥·¸É ¡¨²Ó´μ£μ ·¥¶·¥¸¸μ· É· ´¸±·¨¶Í¨μ´´μ£μ Ë ±Éμ· MBF. ‚ ¶·μɨ¢μ¶μ²μ¦´μ¸ÉÓ CLB6-³Š Ê·μ¢¥´Ó CLB5-³Š ´¥ Ê¢¥²¨Î¨¢ ¥É¸Ö ¢ μÉ¢¥É ´ ·¥¶²¨± Í¨μ´´Ò° ¸É·¥¸¸. ˆ´Ò³¨ ¸²μ¢ ³¨, ÌμÉÖ CLB5-³Š ¶μ¸ÉμÖ´´μ ¶·¨¸ÊÉ¸É¢Ê¥É ¢ ɥΥ´¨¥ ±·¨§¨¸ ·¥¶²¨± ͨ¨, ¸¨´É¥§ Clb5 ´¥ ¶·μ¨¸Ì줨É. ‚ μÉ¢¥É
´ £¥´μÉμ±¸¨Î¥¸±¨° ¸É·¥¸¸ ¸É ¡¨²¨§¨·Ê¥É¸Ö ¶Ê² ´¥¸É ¡¨²Ó´μ° Ëμ·³Ò Clb5.
Œμ¦´μ ¶·¥¤¶μ²μ¦¨ÉÓ, ÎÉμ ·¥ ±É¨¢ ꬅ MBF ¢ μÉ¢¥É ´ £¥´μÉμ±¸¨Î¥¸±¨°
¸É·¥¸¸ ¶·μ¨¸Ìμ¤¨É Éμ²Ó±μ Ê ´¥±μÉμ·ÒÌ £¥´μ¢, ±μÉμ·Ò¥ Ô±¸¶·¥¸¸¨·ÊÕÉ¸Ö ¶μ¤
±μ´É·μ²¥³ MBF ¢ ‘É ·É¥. „ ´´Ò¥ μ ·¥£Ê²Öͨ¨ S-ͨ±²¨´μ¢ Clb5 ¨ Clb6 ¢
μÉ¢¥É ´ £¥´μÉμ±¸¨Î¥¸±¨° ¸É·¥¸¸ ¤μ¶μ²´ÖÕÉ ¤ ´´Ò¥ μ Î¥±¶μ°´É-±μ´É·μ²¥ ·¥£Ê²ÖÉμ· DDK-±¨´ §Ò Dbf4 ¨ ¸Ê¡¸É· É CDK1 Å Sld3, É ±¦¥ ´¥μ¡Ì줨³ÒÌ
¤²Ö ¨´¨Í¨ ͨ¨ ¨ ¶·μÌ즤¥´¨Ö Ë §Ò S [146].
ˆ§¢¥¸É´μ ¤¢ É· ´¸±·¨¶Í¨μ´´ÒÌ ·¥¶·¥¸¸μ· Å Whi5 ¨ Nrm1 É· ´¸±·¨¶Í¨μ´´ÒÌ Ë ±Éμ·μ¢ SBF ¨ MBF [160Ä162]. ¥¶·¥¸¸μ· Whi5 ¶μ¤ ¢²Ö¥É SBF§ ¢¨¸¨³ÊÕ É· ´¸±·¨¶Í¨Õ ¢ · ´´¥° G1 ¤μ ¢¸Éʶ²¥´¨Ö ¢ ´μ¢Ò° ͨ±² ¤¥²¥´¨Ö,
Nrm1 ¸²Ê¦¨É ±μ·¥¶·¥¸¸μ·μ³ MBF ¢´¥ Ë §Ò G1. ƒ¥´Ò, Ô±¸¶·¥¸¸¨Ö ±μÉμ·ÒÌ § ¢¨¸¨É μÉ Ë ±Éμ· MBF (´μ ´¥ SBF), ¶μ-¢¨¤¨³μ³Ê, ·¥£Ê²¨·ÊÕɸÖ
18
·¥¶²¨± ɨ¢´Ò³ Î¥±¶μ°´Éμ³. ‚ μÉ¢¥É ´ ·¥¶²¨± ɨ¢´Ò° ¸É·¥¸¸ ¢ ±²¥É±¥ ¶μ¤¤¥·¦¨¢ ¥É¸Ö MBF-§ ¢¨¸¨³ Ö É· ´¸±·¨¶Í¨Ö, Nrm1 ¨´ ±É¨¢¨·Ê¥É¸Ö ¸¶μ¸μ¡μ³, § ¢¨¸¨³Ò³ μÉ ±¨´ §Ò Dun1, ¢ ¸¢μÕ μÎ¥·¥¤Ó ±É¨¢¨·Ê¥³μ° ±¨´ §μ°
Rad53 [163]. ·¨³¥·μ³ É· ´¸±·¨¶Í¨μ´´μ£μ μÉ¢¥É É ±¦¥ ¸²Ê¦¨É ¨´ ±É¨¢ ꬅ Dun1-§ ¢¨¸¨³Ò³ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥³ É· ´¸±·¨¶Í¨μ´´μ£μ ·¥¶·¥¸¸μ· Crt1, ¢¥¤ÊÐ Ö ± ±É¨¢ ͨ¨ £¥´μ¢, ¨´¤Êͨ·μ¢ ´´ÒÌ ¶μ¢·¥¦¤¥´¨Ö³¨ „Š [164].
¤´ ±μ ·¥£Ê²ÖÍ¨Ö Ô±¸¶·¥¸¸¨¨ ¨´¤Êͨ¡¥²Ó´ÒÌ ¶μ¢·¥¦¤¥´¨Ö³¨ „Š £¥´μ¢
¸²μ¦´ ¨ ¢±²ÕÎ ¥É ¤·Ê£¨¥ É· ´¸±·¨¶Í¨μ´´Ò¥ Ë ±Éμ·Ò [165]. “¶μ³Ö´ÊÉÒ°
¶ÊÉÓ ¢²¨Ö¥É Éμ²Ó±μ ´ μÉ´μ¸¨É¥²Ó´μ ´¥¡μ²ÓÏÊÕ Î ¸ÉÓ ¨§ > 200 É· ´¸±·¨¶Éμ¢,
¨´¤Êͨ·Ê¥³ÒÌ £¥´μÉμ±¸¨Î¥¸±¨³ ¸É·¥¸¸μ³. ɳ¥É¨³, ÎÉμ Î¥±¶μ°´É ¶μ¢·¥¦¤¥´¨° „Š ¢±²ÕÎ ¥É ·¥£Ê²ÖÍ¨Õ ¸¨´É¥§ ·¨¡μ´Ê±²¥μɨ¤·¥¤Ê±É §Ò ¤²Ö ¸¨´É¥§ ¡μ²ÓÏ¥£μ ±μ²¨Î¥¸É¢ ¤’”, ¢ ·¥§Ê²ÓÉ É¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ±¨´ §μ° Dun1
¨ ¤¥£· ¤ ͨ¨ ¨´£¨¡¨Éμ· Sml1 [166Ä168].
”‡ G2
‚ G2/M- ·¥¸Éμ¢ ´´ÒÌ ±²¥É± Ì ¤²Ö ¶μ²´μ° ±É¨¢ ͨ¨ Rad53 „, ¨´¤Êͨ·μ¢ ´´Ò³¨ ˆ ¨ -Ô´¤μ´Ê±²¥ §μ°, ´¥μ¡Ì줨³ ±É¨¢´μ¸ÉÓ CDK1 [83].
Éμ ¸¢Ö§ ´μ ¸ ¶·μÍ¥¸¸¨·μ¢ ´¨¥³ ±μ´Íμ¢ „. Š·μ³¥ Éμ£μ, ±É¨¢ ꬅ Rad53 ¢
·¥§Ê²ÓÉ É¥ ¨¸±Ê¸¸É¢¥´´μ° ±μ²μ± ²¨§ ͨ¨ ¸¥´¸μ·μ¢ Î¥±¶μ°´Éμ¢ (¢ μɸÊɸɢ¨¨
¶μ¢·¥¦¤¥´¨Ö „Š) ´Ê¦¤ ¥É¸Ö ¢ CDK1-§ ¢¨¸¨³μ³ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¨ Rad9 ¢
G2/M- ·¥¸Éμ¢ ´´ÒÌ ±²¥É± Ì [93]. ‘ ¤·Ê£μ° ¸Éμ·μ´Ò, ¨´£¨¡¨·μ¢ ´¨¥ CDK1 ´¥
¡²μ±¨·Ê¥É ƒŒ-¨´¤Êͨ·μ¢ ´´ÊÕ ±É¨¢ Í¨Õ Rad53 [138, 169], ¨ ¤²Ö ±É¨¢ ͨ¨
Rad53 ŒŒ‘ ´¥ ´Ê¦´ ±É¨¢´μ¸ÉÓ CDK1 ¢ ɥΥ´¨¥ G2/M [83]. ’ ±¨³ μ¡· §μ³, ·¥ ±Í¨Ö ´ · §²¨Î´Ò¥ ¶μ¢·¥¦¤¥´¨Ö ¨²¨ ´ „ ´ · §²¨Î´ÒÌ ¸É ¤¨ÖÌ
±²¥Éμδμ£μ ͨ±² μɲ¨Î ¥É¸Ö. ’ ±, „, ¢μ§´¨±Ï¨¥ ¢ G2/M, ¶·¨¢μ¤ÖÉ ± ʳ¥·¥´´μ° ±É¨¢ ͨ¨ Î¥±¶μ°´É , „, ¢μ§´¨±Ï¨¥ ¢ ɥΥ´¨¥ Ë §Ò S, ¶·¨¢μ¤ÖÉ ±
¡μ²¥¥ ¸¨²Ó´μ° ±É¨¢ ͨ¨ Î¥±¶μ°´É § ¸É·Ö¢Ï¥° ·¥¶²¨± ɨ¢´μ° ¢¨²±μ° [170].
μ-¢¨¤¨³μ³Ê, ±É¨¢ Í¨Ö Î¥±¶μ°´É § ¸É·Ö¢Ï¥° ·¥¶²¨± ɨ¢´μ° ¢¨²±μ° ²¨¡μ
´¥ É·¥¡Ê¥É ±É¨¢´μ¸É¨ CDK1, ²¨¡μ Î¥±¶μ°´É´Ò° μÉ¢¥É ´ ¸Éμ²Ó±μ ¸¨²Ó´μ ¢Ò· ¦¥´, ÎÉμ ¶¥·¥±·Ò¢ ¥É ´¥μ¡Ì줨³μ¸ÉÓ ¢ CDK1.
‚ Ô±¸¶¥·¨³¥´É Ì ¸ ³ÊÉ Í¨¥° cdc28-srm ´¥ ¡Ò²μ μ¡´ ·Ê¦¥´μ ´ ·ÊÏ¥´¨° G2 Î¥±¶μ°´É , ¨´¤Êͨ·μ¢ ´´μ£μ ˆ-¶μ¢·¥¦¤¥´¨Ö³¨ „Š ¨ ¡²μ±μ³ ·¥¶²¨± ͨ¨ (ƒŒ), ´μ ´ ·ÊÏ¥´¨Ö G2 μ¸É ´μ¢±¨ ´ ¡²Õ¤ ²¨¸Ó Ê ·¥¶²¨± ɨ¢´ÒÌ ³ÊÉ ´Éμ¢ cdc6-1 ¨ cdc9-1 ¶·¨ ´¥¶¥·³¨¸¸¨¢´μ° É¥³¶¥· ÉÊ·¥. ¤´ ±μ ¨¸¶μ²Ó§μ¢ ´¨¥ ³ÊÉ Í¨¨ cdc28-as1 [F88G] ¶μ± § ²μ, ÎÉμ ¢ Ë §¥ G2 ¤²Ö ±É¨¢ ͨ¨ Œ¥¸1-§ ¢¨¸¨³μ° μ¸É ´μ¢±¨ ¨´¤Êͨ·μ¢ ´´Ò³ -Ô´¤μ´Ê±²¥ §μ° „
É·¥¡Ê¥É¸Ö CDC28 [83]. μ²¥¥ Éμ£μ, Ê ³ÊÉ ´É cdc28-5M, Ê ±μÉμ·μ£μ μɸÊÉ¸É¢μ¢ ² μ¸É ´μ¢± ±²¥Éμδμ£μ ͨ±² , ¨´¤Êͨ·μ¢ ´´ Ö ¶μ¢·¥¦¤¥´¨¥³ „Š,
´ ¡²Õ¤ ²μ¸Ó ¸´¨¦¥´¨¥ ±¨´ §´μ° ±É¨¢´μ¸É¨, ¸¸μͨ¨·μ¢ ´´μ° ¸ Clb2 ¨ ´¥μ¡Ì줨³μ° ¤²Ö ¢ÒÌμ¤ ¨§ ³¨Éμ§ [133]. ’ ±¨³ μ¡· §μ³, · §²¨Î´Ò¥ ²²¥²¨
19
±¨´ §´μ° ¸Ê¡Ñ¥¤¨´¨ÍÒ ¢Ò§Ò¢ ÕÉ · §²¨Î´Ò¥ ¶μ¸²¥¤¸É¢¨Ö ¤¨¸ËÊ´±Í¨¨ CDC28
¨ · §²¨Î´Ò¥ Ë¥´μɨ¶¨Î¥¸±¨¥ ¶·μÖ¢²¥´¨Ö. ·¥¤¸É ¢²Ö¥É ¨´É¥·¥¸ ¨§ÊÎ¥´¨¥
¸¢Ö§¨ ³¥¦¤Ê μ¸μ¡¥´´μ¸ÉÖ³¨ ¸É·Ê±ÉÊ·´μ° μ·£ ´¨§ ͨ¨ ±¨´ §Ò ¨ ¥¥ ËÊ´±Í¨μ´¨·μ¢ ´¨¥³.
Œˆ’‡
‚ ±²¥É± Ì ¶μαÊÕÐ¨Ì¸Ö ¤·μ¦¦¥° ³¨Éμ§ ·¥£Ê²¨·Ê¥É¸Ö ¢ ´¥¸±μ²Ó±¨Ì Éμα Ì. ‘¡μ·± ¢¥·¥É¥´ ±μ´É·μ²¨·Ê¥É¸Ö ¢ G1 ¢¸±μ·¥ ¶μ¸²¥ ‘É ·É , ³¨ÉμɨΥ¸± Ö ¸¥£·¥£ Í¨Ö Ì·μ³μ¸μ³ ±μ´É·μ²¨·Ê¥É¸Ö ¶μ§¤´¥¥ ´ £· ´¨Í¥ ®³¥É Ë § Ä
´ Ë § ¯. ·¨ ´¥¶· ¢¨²Ó´μ° ¸¡μ·±¥ ¢¥·¥É¥´ ¨²¨ ¶·¨ μɸÊɸɢ¨¨ ¸¢Ö§¨
³¥¦¤Ê ³¨±·μÉ·Ê¡μα ³¨ ¨ ±¨´¥ÉμÌμ· ³¨ μ¸ÊÐ¥¸É¢²Ö¥É¸Ö § ¤¥·¦± ¶¥·¥Ìμ¤ ¢ ´ Ë §Ê. Š·μ³¥ Éμ£μ, ±μ´É·μ²¨·Ê¥É¸Ö É ±¦¥ ¢ÒÌμ¤ ¨§ ³¨Éμ§ . §²¨Î´Ò¥
¸É ¤¨¨ ³¨Éμ§ μ·±¥¸É·ÊÕÉ¸Ö ¤¢Ê³Ö ¨²¨ ¡μ²¥¥ ±μ³¶²¥±¸ ³¨ CDC28/‚-ͨ±²¨´.
¥±μÉμ·Ò¥ ¨§ ÔÉ¨Ì Ëμ·³ (CDC28/Clb3 ¨ CDC28/Clb4) ´¥μ¡Ì줨³Ò ¤²Ö ¨´¨Í¨ ͨ¨ ³¨Éμ§ ¨ μ¡· §μ¢ ´¨Ö ³¨ÉμɨΥ¸±μ£μ ¢¥·¥É¥´ , ¤·Ê£¨¥ (CDC28/Clb1
¨ CDC28/Clb2) ´¥μ¡Ì줨³Ò ¤²Ö ¢ÒÌμ¤ ¨§ ³¨Éμ§ ¨ § ¢¥·Ï¥´¨Ö ±²¥Éμδμ£μ ͨ±² .
„²Ö ¶·μÌ즤¥´¨Ö £· ´¨ÍÒ ³¥¦¤Ê ³¥É Ë §μ° ¨ ´ Ë §μ° É·¥¡Ê¥É¸Ö ¤¥£· ¤ ꬅ ¨´£¨¡¨Éμ· · ¸Ì즤¥´¨Ö ¸¥¸É·¨´¸±¨Ì Ì·μ³ É¨¤ Pds1. Œ¨ÉμɨΥ¸± Ö Ëμ·³ CDK1 ÊÎ ¸É¢Ê¥É ¢ ±É¨¢ ͨ¨ ¶·μÉ¥ ¸μ³Ò APC/CCdc20 ¢ ·¥§Ê²ÓÉ É¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ·¥£Ê²ÖÉμ·´μ° ¸Ê¡Ñ¥¤¨´¨ÍÒ Cdc20 ¨ ¶μ¸²¥¤ÊÕÐ¥°
Ê¡¨±¢¨É¨´-§ ¢¨¸¨³μ° ¤¥£· ¤ ͨ¨ ´ Ë §´μ£μ ¨´£¨¡¨Éμ· Pds1 ¨ ͨ±²¨´μ¢
Clb5 ¨ Clb3. —¥±¶μ°´É ¶μ¢·¥¦¤¥´¨° „Š ¢Ò§Ò¢ ¥É § ³¥¤²¥´¨¥ ³¨Éμ§ ¶μ¸·¥¤¸É¢μ³ ¨´£¨¡¨·μ¢ ´¨Ö Ê¡¨±¢¨É¨´¨§ ͨ¨ Pds1, ¢ ·¥§Ê²ÓÉ É¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ¸¥±Ê·¨´ Pds1 ±¨´ §μ° CDK1 [171]. ”μ¸Ëμ·¨²¨·μ¢ ´´Ò° ¸¥±Ê·¨´
Pds1 ʤ¥·¦¨¢ ¥É ¸¥¶ · §Ê Esp1 [172], ´¥μ¡Ì줨³ÊÕ ¤²Ö · ¸Ð¥¶²¥´¨Ö μ¤´μ° ¨§ ¸Ê¡Ñ¥¤¨´¨Í ±μ£¥§¨´μ¢μ£μ ±μ³¶²¥±¸ (Med1p-Scc1p), μÉ¢¥É¸É¢¥´´μ£μ
§ ±μ£¥§¨Õ Ì·μ³ É¨¤. ‚Éμ·μ° ¶ÊÉÓ ¢±²ÕÎ ¥É Rad53-§ ¢¨¸¨³μ¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ Cdc20, ±μÉμ·μ¥ ¨´£¨¡¨·Ê¥É ¢§ ¨³μ¤¥°¸É¢¨¥ ³¥¦¤Ê Cdc20 ¨ Pds1 [173]
¨ É ±¦¥ μ¶μ¸·¥¤Ê¥É ¨´¤Êͨ¡¨²Ó´μ¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ¸Ê¡Ñ¥¤¨´¨ÍÒ ±μ£¥§¨´μ¢μ£μ ±μ³¶²¥±¸ [135].
S-¸¶¥Í¨Ë¨Î¥¸±¨¥ ͨ±²¨´Ò Clb5,6 ¢ · ´´¥° Ë §¥ S μ¡¥¸¶¥Î¨¢ ÕÉ § £·Ê§±Ê
±μ£¥§¨´μ¢ÒÌ ±μ³¶²¥±¸μ¢ ´ Ì·μ³ É¨´. ‚ ´¥¢μ§³ÊÐ¥´´μ° Ë §¥ S ÔÉμÉ ³¥Ì ´¨§³ ¤¥°¸É¢Ê¥É ¶ · ²²¥²Ó´μ ¸ Pds1 ¤²Ö μ¡¥¸¶¥Î¥´¨Ö ±μ£¥§¨¨ ¨ ¤μ¸É ÉμÎ¥´ ¤²Ö
¶μ¤¤¥·¦ ´¨Ö ¸¥¸É·¨´¸±¨Ì Ì·μ³ É¨¤ ¢³¥¸É¥. ‚ ¸²ÊÎ ¥ ´ ·ÊÏ¥´¨Ö ¶·μÌ즤¥´¨Ö
·¥¶²¨± ɨ¢´μ° ¢¨²±¨ μ¡¥ ËÊ´±Í¨¨ Å ÔËË¥±É¨¢´ Ö § £·Ê§± ±μ£¥§¨´ (ËÊ´±Í¨Ö Clb5 ¨ Clb6) ¨ § Шɴ Ö (ËÊ´±Í¨Ö Pds1) Å ´¥μ¡Ì줨³Ò ¤²Ö ʸ¶¥Ï´μ°
±μ£¥§¨¨ [174].
‚ÒÌμ¤ ¨§ ³¨Éμ§ ¸¸μͨ¨·Ê¥É¸Ö ¸ ¨´ ±É¨¢ ͨ¥° Cdc28/Clb2. ‚ ʸ²μ¢¨ÖÌ
μ¸É ´μ¢±¨ ±²¥Éμδμ£μ ͨ±² ¢ G2/M ±¨´ § Rad53 ¶μ¤¤¥·¦¨¢ ¥É ¢Ò¸μ±ÊÕ
20
±¨´ §´ÊÕ ±É¨¢´μ¸ÉÓ CDK1 ¶μ¸·¥¤¸É¢μ³ ¨´£¨¡¨·μ¢ ´¨Ö ±¨´ §Ò Cdc5, ÊÎ ¸É¢ÊÕÐ¥° ¢ ¤¥£· ¤ ͨ¨ ͨ±²¨´μ¢ ¨ ¢ ¢ÒÌ줥 ¨§ ³¨Éμ§ [171].
‚‘‘’‚‹…ˆ… ˆ „’–ˆŸ
·¨ ±É¨¢ ͨ¨ Î¥±¶μ°´É „ ±²¥É±¨ μ¸É ÕÉ¸Ö ·¥¸Éμ¢ ´´Ò³¨ ¤²¨É¥²Ó´μ¥ ¢·¥³Ö μ±μ²μ Ï¥¸É¨ ͨ±²μ¢ ¤¥²¥´¨Ö (12Ä15 Î). ·¨ ÔÉμ³ μ¸´μ¢´μ° ³¥Ì ´¨§³ μ¸É ´μ¢±¨ Å ¶·¥¤μÉ¢· Ð¥´¨¥ ¤¥£· ¤ ͨ¨ ¸¥±Ê·¨´ Pds1 ±μ³¶²¥±¸μ³
APCCdc20 . ‚μ§μ¡´μ¢²¥´¨¥ ¤¥²¥´¨Ö ¢ ¸²ÊÎ ¥ ·¥¶ · ͨ¨ ¶μ¢·¥¦¤¥´¨Ö ´ §Ò¢ ¥É¸Ö ¢μ¸¸É ´μ¢²¥´¨¥³. ¤´ ±μ ¤ ¦¥ ¢ μɸÊɸɢ¨¨ ·¥¶ · ͨ¨ ±²¥É±¨ ¸¶μ¸μ¡´Ò μɱ²ÕΨÉÓ Î¥±¶μ°´É ¨ ¢μ§μ¡´μ¢¨ÉÓ ¤¥²¥´¨¥ ¸ ¶μ³μÐÓÕ ³¥Ì ´¨§³ ,
´ §¢ ´´μ£μ ¤ ¶É ͨ¥° [84, 175Ä177].
‚μ¸¸É ´μ¢²¥´¨¥ μÉ Î¥±¶μ°´É μ¸ÊÐ¥¸É¢²ÖÕÉ Ëμ¸Ë É §Ò Ptc2, Ptc3 ¨ Pph3
¢ ·¥§Ê²ÓÉ É¥ ¤¥Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö Rad53 [42, 178]. Š²¥É±¨ ¤¨±μ£μ ɨ¶ ¢μ¸¸É ´ ¢²¨¢ ÕÉ¸Ö ¸¶Ê¸ÉÖ 40 ³¨´ ¶μ¸²¥ 3-Î ¸μ¢μ° ¨´±Ê¡ ͨ¨ ¸ ƒŒ ¨, ± ± ¶μ± §Ò¢ ¥É FACS ´ ²¨§, § ¢¥·Ï ÕÉ ¶μ²´Ò° ¸¨´É¥§ „Š [138]. ‚ ±²¥É± Ì ¤¨±μ£μ
ɨ¶ ±¨´ § Rad53 ¢ μ¸´μ¢´μ³ ¤¥Ëμ¸Ëμ·¨²¨·μ¢ ´ ¸¶Ê¸ÉÖ 1 Î ¶μ¸²¥ μ¸¢μ¡μ¦¤¥´¨Ö μÉ ƒŒ- ·¥¸É ¨ ¶μÎɨ ¶μ²´μ¸ÉÓÕ ¤¥Ëμ¸Ëμ·¨²¨·μ¢ ´ ¸¶Ê¸ÉÖ 2 Î
¶μ¸²¥ ¢Ò¸¢μ¡μ¦¤¥´¨Ö. ŒÊÉ ´É cdc28-5M É ±¦¥ § ¢¥·Ï ² ¸¨´É¥§ „Š ¸¶Ê¸ÉÖ
40 ³¨´, ´μ ¢ÒÌμ¤ ¨§ Ë §Ò Œ ¶·μÌ줨² ³¥¤²¥´´¥¥, Î¥³ ¢ ±²¥É± Ì ¤¨±μ£μ ɨ¶ .
“ ³ÊÉ ´É cdc28-as1 ¸É¥¶¥´Ó ¤¥Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö Rad53 ¸μμÉ¢¥É¸É¢μ¢ ² É ±μ¢μ° Ê ±²¥Éμ± ¤¨±μ£μ ɨ¶ .
μÖ¢¨²¨¸Ó ¤ ´´Ò¥ μ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¨ Rad53 ±¨´ §μ° CDK1. Rad53
¨³¥¥É 13 ¸ °Éμ¢ ¢ÉμËμ¸Ëμ·¨²¨·μ¢ ´¨Ö ¨ 14 ¸ °Éμ¢ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ±¨´ § ³¨, ¢ Éμ³ Î¨¸²¥ Œ¥¸1, Cdc5 ¨ CDK1 [39]. ±É¨¢´μ¸ÉÓ ±¨´ §Ò Cdc5, ±É¨¢¨·ÊÕÐ¥° ¢ÒÌμ¤ ¨§ ³¨Éμ§ , μ£· ´¨Î¨¢ ¥É¸Ö Ë § ³¨ G2/M. ‚ μÉ¢¥É ´ ¶μ¢·¥¦¤¥´¨Ö „Š ÔÉ ±¨´ § Ëμ¸Ëμ·¨²¨·Ê¥É¸Ö Rad53-§ ¢¨¸¨³Ò³ ¸¶μ¸μ¡μ³ [179].
Ò²μ ¶μ± § ´μ, ÎÉμ Cdc5 ´¥μ¡Ì줨³ ¤²Ö ¤ ¶É ͨ¨ [176]. ”μ¸Ëμ·¨²¨·μ¢ ´¨¥ ‘-±μ´Í Rad53 ¶μ S774 ±¨´ §μ° CDK1 ¨ S789, S791 ±¨´ §μ° Cdc5 § ¢¨¸¨É μÉ Ë §Ò ±²¥Éμδμ£μ ͨ±² , μ¡´ ·Ê¦¨¢ ¥É¸Ö ¢ μɸÊɸɢ¨¨ ¶μ¢·¥¦¤¥´¨Ö
¢ Ë § Ì G1, G2 ¨ M ¨ ¨³¥¥É ¶¨± Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ¢ ³¨É짥. ”μ¸Ëμ·¨²¨·μ¢ ´¨¥ ´¥ ¢²¨Ö¥É ´ ±É¨¢ Í¨Õ Î¥±¶μ°´É [180, 181], ´μ ¶·¥¤μÉ¢· Ð ¥É
¤ ¶É Í¨Õ Î¥±¶μ°´É [180], É ±¦¥ ¢ ¦´μ ¤²Ö ËÊ´±Í¨μ´¨·μ¢ ´¨Ö Rad53 ¢
·¥£Ê²Öͨ¨ ³μ·Ëμ£¥´¥§ ±²¥É±¨ [181], μ¡¥¸¶¥Î¨¢ ÕÐ¥£μ ¢Ò¦¨¢ ¥³μ¸ÉÓ ±²¥É±¨
¢ ¶·μÍ¥¸¸¥ ·¥¶²¨± ɨ¢´μ£μ ¸É·¥¸¸ . ·¥¤¶μ² £ ¥É¸Ö, ÎÉμ ÔÉμ ¤μ¶μ²´¨É¥²Ó´μ¥
Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ μ¡¥¸¶¥Î¨¢ ¥É Éμ´±ÊÕ ´ ¸É·μ°±Ê Ê·μ¢´Ö Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö Rad53, μÉ ±μÉμ·μ£μ § ¢¨¸¨É ±É¨¢ ꬅ ±¨´ §Ò Rad53, ¥¥ ¶μ¤¤¥·¦ ´¨¥ ¨
¤ ¶É ͨÖ. ‚ Ë §¥ S ¢ μɸÊɸɢ¨¨ ¤μ¶μ²´¨É¥²Ó´μ£μ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ±¨´ § ³¥´¥¥ ÎÊ¢¸É¢¨É¥²Ó´ ± μ´„Š, ¢μ§´¨± ÕÐ¥° ¢ ¶·μÍ¥¸¸¥ ·¥¶²¨± ͨ¨,
´ ¡²Õ¤ ¥É¸Ö ³¥´¥¥ ¸¨²Ó´Ò° μÉ¢¥É ´ ¶μ¢·¥¦¤¥´¨Ö „Š [182, 183]. ‚ Éμ ¦¥
¢·¥³Ö μ´ ¢Ò¸μ±μÎÊ¢¸É¢¨É¥²Ó´ ± ¶μ¢·¥¦¤¥´¨Ö³ „Š ¢ G2/M. Š²¥É±¨ ¤¨±μ£μ
21
ɨ¶ ³μ£ÊÉ ¤ ¶É¨·μ¢ ÉÓ¸Ö ¢ G2/M ¶·¨ ´ ²¨Î¨¨ μ¤´μ£μ, ´μ ´¥ ¤¢ÊÌ ¶μ¢·¥¦¤¥´¨° „Š [9].
Œ”ƒ……‡ ˆ –ˆ’Šˆ…‡
μÎ±μ¢ ´¨¥. Š²ÕÎ¥¢ Ö ±μ´É·μ²Ó´ Ö Éμα ¢ ¶·μÍ¥¸¸¥ ¶μÎ±μ¢ ´¨Ö · ¸¶μ² £ ¥É¸Ö ¢ ‘É ·É¥, ¢ ÔÉμ° Éμα¥ ´ ¨´¨Í¨ Í¨Õ μ¡· §μ¢ ´¨Ö ¶μα¨ ¢²¨ÖÕÉ
¸μ¸É ¢ ¸·¥¤Ò ¨ ¶μ²μ¢Ò¥ Ë¥·μ³μ´Ò. ‚Éμ·μ° ¢ ¦´Ò° ³μ³¥´É ±μ´É·μ²Ö, ´ §¢ ´´Ò° Î¥±¶μ°´Éμ³ ¶μÎ±μ¢ ´¨Ö, ±μμ·¤¨´¨·Ê¥É μ¡· §μ¢ ´¨¥ ¨ ·μ¸É ¶μα¨
¸ ¶μ¸²¥¤ÊÕШ³¨ ¶·μÍ¥¸¸ ³¨ Ö¤¥·´μ£μ ¤¥²¥´¨Ö. ÉμÉ Î¥±¶μ°´É ·¥£Ê²¨·Ê¥É
¶¥·¥±²ÕÎ¥´¨¥ ±¨´ §Ò ¸ Ëμ·³Ò G1 (Cdc28/Cln) ´ G2 (Cdc28/Clb). „²Ö ¢μ§´¨±´μ¢¥´¨Ö ¶μα¨, ´ Ψ´ Ö ¸ ±μ´Í Ë §Ò G1, ´¥μ¡Ì줨³ ¸É ¡¨²Ó´ Ö ¶μ²Ö·¨§ ꬅ ±É¨´μ¢μ£μ ͨÉμ¸±¥²¥É , ¨ ÔÉμÉ ¶·μÍ¥¸¸ ±μ´É·μ²¨·Ê¥É¸Ö ͨ±²¨´ ³¨
Cln1,2. ‚ G1 ¶·μ¨¸Ìμ¤¨É Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ±¨´ §μ° Swe1 ɨ·μ§¨´ 19
(CDK1Y19ph). ‚ G2 ¥£μ ¤¥Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ Ëμ¸Ë É §μ° Mih1 ¢Ò§Ò¢ ¥É
Ê¢¥²¨Î¥´¨¥ ±¨´ §´μ° ±É¨¢´μ¸É¨. ‚ ¸²ÊÎ ¥ ´ ·ÊÏ¥´¨Ö ¶μÎ±μ¢ ´¨Ö (´ ¶·¨³¥·,
Ê ³ÊÉ ´É cdc24-ts) ¤²Ö ³μ·Ëμ²μ£¨Î¥¸±μ£μ Î¥±¶μ°´É Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ɨ·μ§¨´ Y19 ±·¨É¨Î´μ. —¥±¶μ°´É § ³¥¤²Ö¥É ¤¥²¥´¨¥ Ö¤· ¢ G2 ¶·¨³¥·´μ ´ 2 Î
(¢·¥³Ö μ¤´μ£μ ±²¥Éμδμ£μ ¤¥²¥´¨Ö) ¨ ¶·¥¤μÉ¢· Ð ¥É ¢μ§´¨±´μ¢¥´¨¥ ¡¨Ö¤¥·´ÒÌ ±²¥Éμ±. ‡ ¤¥·¦± ±²¥Éμδμ£μ ¤¥²¥´¨Ö ¶μ²´μ¸ÉÓÕ μɸÊÉ¸É¢Ê¥É ¶·¨ ¢¢¥¤¥´¨¨ ³ÊÉ Í¨¨ cdc28-Y19F, ¶·¥¤μÉ¢· Ð ÕÐ¥° Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ɨ·μ§¨´ ,
¨²¨ ¶·¨ ¸¢¥·ÌÔ±¸¶·¥¸¸¨¨ MIH1 [139]. Š·μ³¥ Éμ£μ, Ë¥´μɨ¶ ¶¨± ²Ó´μ£μ ·μ¸É ¨ § ¤¥·¦± ¤¥²¥´¨Ö Ö¤· Î ¸É¨Î´μ ¸Ê¶·¥¸¸¨·ÊÕÉ¸Ö ¤¥²¥Í¨¥° SWE1 ¨²¨
¸¢¥·ÌÔ±¸¶·¥¸¸¨¥° £¥´ CLB2.
CDK1 ÊÎ ¸É¢Ê¥É ´¥ Éμ²Ó±μ ¢ ¨´¨Í¨ ͨ¨ ¨ ¶μ¤¤¥·¦ ´¨¨ ¶μ²Ö·¨§μ¢ ´´μ£μ
·μ¸É , ´μ ¨ ¢ ¤μ¸É ¢±¥ ¢¥§¨±Ê² ¸ ¡¥²± ³¨, ´¥μ¡Ì줨³Ò³¨ ¤²Ö ·μ¸É ³¥³¡· ´Ò.
‚¥§¨±Ê²Ò Å ÔÉμ ¶Ê§Ò·Ó±¨, ±μÉμ·Ò¥ μ¡· §ÊÕÉ¸Ö ¨§ ³¥³¡· ´ Ô´¤μ¶² §³ ɨΥ¸±μ£μ ·¥É¨±Ê²Ê³ () ¨ ¸μ¤¥·¦ É Ë¥·³¥´ÉÒ, ¤μ¸É ¢²Ö¥³Ò¥ ¢ · §´Ò¥ μɤ¥²Ò
±²¥É±¨, ´ ¶·¨³¥·, ± ³¥¸ÉÊ ·μ¸É ¶μα¨. ’ ±¨³ μ¡· §μ³, CDK1 ¨£· ¥É ¢ ¦´ÊÕ ·μ²Ó ¢ ±μμ·¤¨´ ͨ¨ ·μ¸É ±²¥ÉμÎ´μ° ¸É¥´±¨ ¸ ¶·μÌ즤¥´¨¥³ ±²¥Éμδμ£μ
ͨ±² [184].
Œ¥Ì ´¨§³ ¨´£¨¡¨Éμ·´μ£μ Ëμ¸Ëμ·¨²¨·μ¢ ´¨Ö ¢Ò¸μ±μ ±μ´¸¥·¢ ɨ¢¥´ ¨
±μ´É·μ²¨·Ê¥É ¤¥²¥´¨¥ Ö¤· Ê ¤·Ê£¨Ì Ôʱ ·¨μÉ, ¢±²ÕÎ Ö S. ·ombe, Ê ±μÉμ·ÒÌ
ÔÉμÉ ¶ÊÉÓ ·¥£Ê²¨·Ê¥É Î¥±¶μ°´É ·¥¶²¨± ͨ¨ „Š, É ±¦¥ ¨§¢¥¸É´ ¥£μ ·μ²Ó
¢ Î¥±¶μ°´É¥ ¶μ²Ö·´μ¸É¨ ±²¥Éμδμ£μ ·μ¸É [185, 186]. ±É¨¢ Í¨Ö Î¥±¶μ°´É Ê
¤·μ¦¦¥° S. pombe ¨ ¢Ò¸Ï¨Ì Ôʱ ·¨μÉ ¶·μ¨¸Ìμ¤¨É ¢ ·¥§Ê²ÓÉ É¥ ¨´£¨¡¨·μ¢ ´¨Ö CDK1 ¶μ¸·¥¤¸É¢μ³ ·¥£Ê²Öͨ¨ Ëμ¸Ë É §Ò Cdc25 ¨ ¸³¥Ð¥´¨Ö ¡ ² ´¸ μÉ
±É¨¢´μ° ¤¥Ëμ¸Ëμ·¨²¨·μ¢ ´´μ° Ëμ·³Ò ± ´¥ ±É¨¢´μ° Ëμ¸Ëμ·¨²¨·μ¢ ´´μ°
Ëμ·³¥ CDK1Y19ph. μ²¥¥ Éμ£μ, Ê ¢Ò¸Ï¨Ì Ôʱ ·¨μÉ ¤²Ö ¤ ²Ó´¥°Ï¥£μ ¨´£¨¡¨·μ¢ ´¨Ö ±É¨¢´μ¸É¨ CDK1 ±É¨¢¨·Ê¥É¸Ö ¡¥²μ± ·53, ¢Ò§Ò¢ ÕШ° ¨´¤Ê±Í¨Õ
Ô±¸¶·¥¸¸¨¨ ¨´£¨¡¨Éμ·μ¢ ±¨´ §Ò CDK1, É ±¨Ì ± ± ·21. ¤´ ±μ ±²¥É±¨ ¤·μ¦22
¦¥° S. cerevisiae μ¡Òδμ μ¸É ´ ¢²¨¢ ÕÉ Í¨±² ¤¥²¥´¨Ö ¶·¨ ¢Ò¸μ±μ° ±É¨¢´μ¸É¨ CDK1, ¨ ¨´£¨¡¨Éμ·´μ¥ Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ CDK1Y19ph ´¥ É·¥¡Ê¥É¸Ö ¤²Ö
ÔËË¥±É¨¢´μ° μ¸É ´μ¢±¨ ±²¥Éμδμ£μ ͨ±² [139, 187].
ʱ ·¨μɨΥ¸± Ö ±²¥É± ¸μ¤¥·¦¨É · §²¨Î´Ò¥ ³ ±·μ³μ²¥±Ê²Ö·´Ò¥ ¸É·Ê±ÉÊ·Ò, É ±¨¥ ± ± ±É¨´, Éʡʲ¨´, ¶·μ³¥¦ÊÉμδҥ ˨² ³¥´ÉÒ, ¸¥¶É¨´μ¢Ò° ͨÉμ¸±¥²¥É, ´¥μ¡Ì줨³Ò¥ ¤²Ö ³μ·Ëμ£¥´¥§ , É· ´¸¶μ·É ¢¨§¨±Ê², ¤¥²¥´¨Ö Ö¤· ¨
ͨÉ챨´¥§ . —Éμ ¸± ´¨·Ê¥É ³μ·Ëμ²μ£¨Î¥¸±¨° Î¥±¶μ°´É? μ± § ´μ, ÎÉμ μ¤´μ°
¨§ É ±¨Ì ¸É·Ê±ÉÊ· Ö¢²Ö¥É¸Ö ¸¥¶É¨´ [188]. ‘¥¶É¨´μ¢Ò¥ ³ÊÉ ´ÉÒ μ¸É ´ ¢²¨¢ ÕÉ
¤¥²¥´¨¥ ¢ Ë §¥ ¶¨± ²Ó´μ£μ ·μ¸É ¨ ¶·μÖ¢²ÖÕÉ § ¤¥·¦±Ê Ö¤¥·´μ£μ ¤¥²¥´¨Ö,
¤¥³μ´¸É·¨·ÊÖ § ¤¥·¦±Ê ±É¨¢ ͨ¨ G2-±¨´ §Ò. ‘ ¤·Ê£μ° ¸Éμ·μ´Ò, ¢ ¸²ÊÎ ¥
´ ·ÊÏ¥´¨Ö ¶·μÍ¥¸¸ ¢μ§´¨±´μ¢¥´¨Ö ¶μα¨ ¢ ±²¥É± Ì cdc24-ts ´ ¡²Õ¤ ¥É¸Ö
´ ·ÊÏ¥´¨¥ · ¸¶·¥¤¥²¥´¨Ö ¸¥¶É¨´ .
‘¥¶É¨´μ¢Ò¥ ¡¥²±¨ (Cdc10, Cdc11, Cdc12, Cdc3) μ¡· §ÊÕÉ ¡²μ±¨, ¨§ ±μÉμ·ÒÌ ¸μ¡¨· ÕÉ¸Ö Ë¨² ³¥´ÉÒ, μ¡· §ÊÕШ¥ ¶² ÉËμ·³Ê ¤²Ö ¸¡μ·±¨ ¤·Ê£¨Ì
¡¥²±μ¢ (´ ¶·¨³¥·, Myo1), ¨ ±μ²ÓÍ¥¢ÊÕ ¸É·Ê±ÉÊ·Ê, Ö¢²ÖÕÐÊÕ¸Ö ¤¨ËËʧ´Ò³
¡ ·Ó¥·μ³, ¢ ¦´Ò³ ¤²Ö ¶μ²Ö·¨§μ¢ ´´μ£μ ·μ¸É . ‘¥¶É¨´ ÊÎ ¸É¢Ê¥É ¢ ¶μ¤¤¥·¦ ´¨¨ ¸¨³³¥É·¨Î´μ£μ · ¸¶·¥¤¥²¥´¨Ö ´¥±μÉμ·ÒÌ · ¸É¢μ·¨³ÒÌ ¡¥²±μ¢, É ±¨Ì
± ± Myo2, Sec3, Spa2, ´¥μ¡Ì줨³ÒÌ ¤²Ö ¶μ²Ö·¨§μ¢ ´´μ£μ ·μ¸É ¶μα¨ [189],
É ±¦¥ ¸¶μ¸μ¡¸É¢Ê¥É ±μ³¶ ·É³¥´É ²¨§ ͨ¨ ³Š [190, 191]. ‘¥¶É¨´μ¢Ò°
μ¡·ÊÎ ´Ê¦¥´ ¤²Ö ¸¡μ·±¨ ±É쳨짨´μ¢μ£μ ±μ²ÓÍ (Š) ¢ ¶¥·¥Ï¥°±¥, ´μ ´¥
¤²Ö ¥£μ ¸É ¡¨²¨§ ͨ¨ ¨²¨ ¸Ê¦¥´¨Ö. Š ¸μ¡¨· ¥É¸Ö ´ · ´´¥° ¸É ¤¨¨ ±²¥Éμδμ£μ ¤¥²¥´¨Ö ¢ ¸ °É¥ ¶μÎ±μ¢ ´¨Ö. ‚ ¶μ§¤´¥° ´ Ë §¥ Myo1-§ ¢¨¸¨³Ò³
¸¶μ¸μ¡μ³ ¶·¨¸μ¥¤¨´Ö¥É¸Ö F- ±É¨´ (Act1) ¨ ¡¥²μ± Igg1. ‚ ±μ´Í¥ ´ Ë §Ò ¶·μ¨¸Ìμ¤¨É ¸¦¨³ ´¨¥ Š, § ¢¨¸¨³μ¥ μÉ F- ±É¨´ . ±É¨¢´μ¸ÉÓ ¸¦¨³ ´¨Ö ±μ²ÓÍ ·¥£Ê²¨·Ê¥É¸Ö ¸¨¸É¥³μ° ¢ÒÌμ¤ ¨§ ³¨Éμ§ MEN (mitotic exit network), ±μÉμ· Ö
μ¡¥¸¶¥Î¨¢ ¥É ¨´ ±É¨¢ Í¨Õ CDK1, ¨´£¨¡¨·ÊÕÐÊÕ ¸¦¨³ ´¨¥ ±μ²ÓÍ .
·¨ ¸¡μ·±¥ ¸¥¶É¨´ Î¥±¶μ°´É μ¸ÊÐ¥¸É¢²Ö¥É ³μ´¨Éμ·¨´£, ±μμ·¤¨´¨·ÊÕШ° ¸¡μ·±Ê ͨÉμ¸±¥²¥É ¨ ´ Î ²μ ³¨Éμ§ [188, 192]. Š²ÕÎ¥¢Ò³¨ Ë¥·³¥´É ³¨
Ö¢²ÖÕÉ¸Ö ±¨´ §Ò Hsl1, Gin4 ¨ Kcc4 [188, 193Ä196]. ‚¸¥ Ôɨ ±¨´ §Ò ²μ± ²¨§μ¢ ´Ò ¢ ±μ²ÓÍ¥ ¶¥·¥Ï¥°± , ¢ ¸ °É¥ ²μ± ²¨§ ͨ¨ ¸¥¶É¨´ . μ¸²¥ ¸¡μ·±¨
¸¥¶É¨´ Hsl1 ±É¨¢¨·Ê¥É¸Ö ¨ § ¶Ê¸± ¥É ¢¸Éʶ²¥´¨¥ ¢ ³¨Éμ§ ¢ ·¥§Ê²ÓÉ É¥ ¨´£¨¡¨·μ¢ ´¨Ö Swe1 [188, 192]. Š¨´ §Ò Ëμ¸Ëμ·¨²¨·ÊÕÉ ¨ ¨´ ±É¨¢¨·ÊÕÉ Swe1,
ÎÉμ ¶·¨¢μ¤¨É ± ±É¨¢ ͨ¨ Cdc28/Clb ±¨´ §, ¨´¤Ê±Í¨¨ ³¨Éμ§ ¨ ¨§μÉ·μ¶´μ³Ê ·μ¸ÉÊ. Š²¥É±¨, ´¥ ¸¶μ¸μ¡´Ò¥ ± ¸¡μ·±¥ ¸¥¶É¨´ ¨²¨ ÊÉ· ɨ¢Ï¨¥ ±¨´ §Ò, ¨³¥ÕÉ ¶·μ¤μ²¦¨É¥²Ó´ÊÕ Ë §Ê G2 ¨ Ì · ±É¥·¨§ÊÕÉ¸Ö £¨¶¥·¶μ²Ö·¨§ ͨ¥°. ÉμÉ Ë¥´μɨ¶ ¸Ê¶·¥¸¸¨·Ê¥É¸Ö ¤¥²¥Í¨¥° SWE1.
¡´ ·Ê¦¥´ ¶·μ¸Éμ° ³¥Ì ´¨§³, ¶μ§¢μ²ÖÕШ° ±¨´ § ³ μ¶·¥¤¥²ÖÉÓ ¸É¥¶¥´Ó
¸¡μ·±¨ ¸¥¶É¨´ [197]. Š¨´ § Hsl1 Å ¡μ²ÓÏμ° ¡¥²μ± (∼ 1500 μ¸É.). ‚ N-±μ´Í¥¢μ³ ÊÎ ¸É±¥ · ¸¶μ² £ ¥É¸Ö ±¨´ §´Ò° ¤μ³¥´ (370 μ¸É.), ¢ ‘-±μ´Í¥¢μ³
ÊÎ ¸É±¥ Å ¨´£¨¡¨·ÊÕШ° ¤μ³¥´ (987Ä1100 μ¸É.), ±μÉμ·Ò° ¸¢Ö§Ò¢ ¥É¸Ö ¸ ±¨´ §´Ò³ ¤μ³¥´μ³ ¨ ¥£μ ¨´£¨¡¨·Ê¥É ( ¢Éμ¨´£¨¡¨·μ¢ ´¨¥). ‚ ÔÉμ° ¦¥ μ¡² ¸É¨,
¢¡²¨§¨ ¨²¨ ¶¥·¥±·Ò¢ Ö ÔÉμÉ ¤μ³¥´, ²¥¦ É ¸ °ÉÒ ¸¢Ö§Ò¢ ´¨Ö ¸ ¸¥¶É¨´ ³¨
23
Cdc12 (987Ä1100 ¨ 1282Ä1400 μ¸É.) ¨ Cdc11 (1000Ä1282 μ¸É.). ‘¢Ö§Ò¢ ´¨¥ ¸
´¥¸±μ²Ó±¨³¨ ¸¥¶É¨´ ³¨ ¶·¨¢μ¤¨É ± ±É¨¢ ͨ¨ Hsl1, μ¡¥¸¶¥Î¨¢ Ö, É ±¨³ μ¡· §μ³, ¶·μÌ즤¥´¨¥ ±²¥Éμδμ£μ ͨ±² . ƒμ³μ²μ£¨ Hsl1, Gin4 ¨ Kcc4 É ±¦¥ ¢§ ¨³μ¤¥°¸É¢ÊÕÉ ¸ ¸¥¶É¨´ ³¨ (Cdc3 ¨ Cdc11/Cdc12 ¸μμÉ¢¥É¸É¢¥´´μ) [194, 198].
¢Éμ·Ò ¶·¥¤¶μ² £ ÕÉ, ÎÉμ ¢¸¥ É·¨ ±¨´ §Ò ¢§ ¨³μ¤¥°¸É¢ÊÕÉ ¸ ¸¥¶É¨´ ³¨ ¨ ±É¨¢¨·ÊÕÉ¸Ö ´ ²μ£¨Î´Ò³ ¸¶μ¸μ¡μ³. ‘μμÉ¢¥É¸É¢ÊÕÐ Ö μ·£ ´¨§ ꬅ ¸¥¶É¨´μ¢
¶μ§¢μ²Ö¥É ±²¥É± ³ ¢¸Éʶ ÉÓ ¢ ¸²¥¤ÊÕÐÊÕ Ë §Ê ±²¥Éμδμ£μ ͨ±² . „¥°¸É¢¨É¥²Ó´μ ²¨ ¶·¨ μ·£ ´¨§ ͨ¨ ¤·Ê£¨Ì ±μ³¶μ´¥´É ¶μ²Ö·´μ¸É¨, É ±¨Ì ± ± ±É¨´,
¶·μ¨¸Ìμ¤¨É ³μ´¨Éμ·¨´£ ¢ ¶·μÍ¥¸¸¥ ±²¥Éμδμ£μ ͨ±² , Ö¢²Ö¥É¸Ö ¢ ¦´Ò³, ´μ
´¥·¥Ï¥´´Ò³ ¢μ¶·μ¸μ³.
’ ±¨³ μ¡· §μ³, ¶·Ö³μ° ³¨Ï¥´ÓÕ ³μ·Ëμ²μ£¨Î¥¸±μ£μ Î¥±¶μ°´É Ö¢²Ö¥É¸Ö
±¨´ § Swe1, ¨´£¨¡¨·ÊÕÐ Ö ±É¨¢´μ¸ÉÓ CDK1. ¤´ ±μ ÔÉμÉ ³¥Ì ´¨§³ ´¥
ËÊ´±Í¨μ´¨·Ê¥É ¢ ¸²ÊÎ ¥ Î¥±¶μ°´É Í¥´É·¨μ²Ö·´ÒÌ ¶² ¸É¨´μ± [199] ¨²¨ Î¥±¶μ°´É , ¨´¤Êͨ·μ¢ ´´μ£μ ¶μ¢·¥¦¤¥´¨Ö³¨ „Š [200], ±μÉμ·Ò° É ±¦¥ μ¸ÊÐ¥¸É¢²Ö¥É μ¸É ´μ¢±Ê ¢ G2. ‘ÊÐ¥¸É¢Ê¥É ¥Ð¥ Î¥±¶μ°´É Í¥²μ¸É´μ¸É¨ ±²¥Éμδμ°
¸É¥´±¨ [201].
„¢¨¦¥´¨¥ Ö¤· . ¥¤ ¢´μ μ¡´ ·Ê¦¥´ ͨÉ춲 §³ ɨΥ¸±¨° ¸¨£´ ² Î¥±¶μ°´É , ±μ´É·μ²¨·ÊÕÐ¥£μ ¶μ²μ¦¥´¨¥ Ö¤· [76]. ·¥¤¶μ² £ ¥É¸Ö, ÎÉμ ¢ Î¥±¶μ°´É´μ° μ¸É ´μ¢±¥ ¶¥·¥¤ ´ Ë §μ° ¸ÊÐ¥¸É¢ÊÕÉ ¤¢ ±μ³¶μ´¥´É : 줨´ Å ¶μ¤ ¢²¥´¨¥ · ¸Ì즤¥´¨Ö Ì·μ³μ¸μ³ (Pds1), ¢Éμ·μ° Å ¶·¥¤μÉ¢· Ð¥´¨¥ ¤¨´¥¨´§ ¢¨¸¨³μ£μ ¤¢¨¦¥´¨Ö ¢¥·¥É¥´ ¢ ¶μαÊ, ±μÉμ·μ¥ ¶·μ¨¸Ìμ¤¨É ¢ ´μ·³¥ ¢ ´ Ë §¥. ‚ ´μ·³¥ ¢ ³¨É짥 ¢§ ¨³μ¤¥°¸É¢¨¥ ¶Ê² ¢¥·¥É¥´ ¸ ±μ·É¥±¸μ³ ¶μα¨
±É¨¢¨·Ê¥É ¸¨¸É¥³Ê ¢ÒÌμ¤ ¨§ ³¨Éμ§ MEN [202, 203], ¢±²ÕÎ ÕÐÊÕ Ëμ¸Ë É §Ê Cdc14, ±μÉμ· Ö § ¶Ê¸± ¥É É¥²μË §Ê ¨ ¶·μÌ즤¥´¨¥ ¢ ¸²¥¤ÊÕШ° ͨ±²
¤¥²¥´¨Ö ±²¥É±¨. ‚ μÉ¢¥É ´ ¶μ¢·¥¦¤¥´¨Ö „Š Œ¥¸1-§ ¢¨¸¨³Ò° Î¥±¶μ°´É
Î¥·¥§ Rad53 ¨ Chk1 ·¥¶·¥¸¸¨·Ê¥É ¶¥·¥¤¢¨¦¥´¨Ö Ö¤· , ¸¸μͨ¨·μ¢ ´´Ò¥ ¢
´μ·³¥ ¸ ¢ÒÌμ¤μ³ ¨§ ´ Ë §Ò. “ 줨´μδÒÌ ³ÊÉ ´Éμ¢ ¢ μɸÊɸɢ¨¨ ¶μ²´μÍ¥´´μ£μ Î¥±¶μ°´É-μÉ¢¥É ¶¶ · É Í¨É춲 §³ ɨΥ¸±μ£μ ³¨±·μÉʡʲ¨´ μ¸ÊÐ¥¸É¢²Ö¥É μ·¨¥´É Í¨Õ ¨ ¤¢¨¦¥´¨¥ Ö¤· ¶μ ´ ¶· ¢²¥´¨Õ ± ±μ´Î¨±Ê ¶μα¨.
…¸²¨ ¶μ²Ö·´μ¥ É¥²μ ¢¥·¥É¥´ SPD (spindle pool body) ¤μ¸É¨£ ¥É ±μ·É¥±¸ ¶μα¨, ¢´ÊÉ·¨Ö¤¥·´Ò° Î¥±¶μ°´É ¥Ð¥ ¢ ¸¨²¥, Cdc14 ³μ¦¥É ´¥ ±É¨¢¨·μ¢ ÉÓ¸Ö ¨ ¶·¥ ´ Ë § ¶·μ¤μ²¦¨É¸Ö, ¶·¨¢μ¤Ö ¢ ·¥§Ê²ÓÉ É¥ ± ³¨£· ͨ¨ ¢¥·¥É¥´ , ¤¢¨£ ÕÐ¥£μ¸Ö ¢§ ¤-¢¶¥·¥¤ ¨ ¶¥·¥¸¥± ÕÐ¥£μ ¶¥·¥Ï¥¥± ¶μα¨. ‚ ´μ·³¥
¸¥¶ · § Esp1 ʤ¥·¦¨¢ ¥É¸Ö ¢ ͨÉ춲 §³¥ ¢¶²μÉÓ ¤μ ´ Ë §Ò, ¶μ¸Éʶ²¥´¨¥ ¥¥ ¢ Ö¤·μ μ¡²¥£Î ¥É¸Ö Pds1 [173], ´μ, ¢¥·μÖÉ´μ, ¥¸ÉÓ ¨ ¤·Ê£μ° ±μ´É·μ²Ó É· ´¸¶μ·É , ¤²Ö ±μÉμ·μ£μ É·¥¡Ê¥É¸Ö Rad53 ¨/¨²¨ Chk1 [204]. –¨É춲 §³ ɨΥ¸± Ö ·μ²Ó Rad53 ¶·μÖ¢²Ö¥É¸Ö É ±¦¥ ¢ ·¥£Ê²Öͨ¨ ³μ·Ëμ²μ£¨Î¥¸±¨Ì ¸μ¡Òɨ° ¶·¨ ·¥¶²¨± ɨ¢´μ³ ¸É·¥¸¸¥, ¢±²ÕÎ Ö Ëμ¸Ëμ·¨²¨·μ¢ ´¨¥ ¸¥¶É¨´ ¨ ¤¥£· ¤ Í¨Õ ±¨´ §Ò Swe1 [53, 205]. ·ÊÏ¥´¨¥ Œ¥¸1 ¶·¨¢μ¤¨É ±
¶μ²´μ³Ê ʸɷ ´¥´¨Õ § ¤¥·¦±¨. ŒÊÉ Í¨¨ rad53Δ, chk1Δ ¨ pds1Δ ¢Ò§Ò¢ ÕÉ
²¨ÏÓ Î ¸É¨Î´μ¥ ¸μ±· Ð¥´¨¥ μ¸É ´μ¢±¨, ¨ Éμ²Ó±μ Ê É·μ°´μ£μ ³ÊÉ ´É μ¸É ´μ¢± μɸÊÉ¸É¢Ê¥É ¶μ²´μ¸ÉÓÕ. μ-¢¨¤¨³μ³Ê, Rad53 ¨ Chk1 ¨³¥ÕÉ ¤·Ê£¨¥
24
³¨Ï¥´¨ ¶μ³¨³μ ¸¥±Ê·¨´ . Š¨´ § CDK1 ¶·¨´¨³ ¥É ÊÎ ¸É¨¥ ¢ ·¥£Ê²Öͨ¨
±É¨¢´μ¸É¨ Esp1 ¨ Rad53.
‘¥£·¥£ ꬅ ³¨ÉμÌμ´¤·¨°. ·μÍ¥¸¸ ¤¥²¥´¨Ö ±²¥É±¨ Ê ¶μαÊÕÐ¨Ì¸Ö ¤·μ¦¦¥° ¸¨³³¥É·¨Î´Ò°, ¨ ¶¥·¥¤ Î μ·£ ´¥²² ¤μÎ¥·´¥° ±²¥É±¥ ¶·¥¤¸É ¢²Ö¥É ¸μ¡μ° ±É¨¢´Ò° ¶·μÍ¥¸¸ ¸¥£·¥£ ͨ¨. ¢´μ³¥·´μ¥ · ¸¶·¥¤¥²¥´¨¥ μ·£ ´¥²²
³¥¦¤Ê ³ É¥·¨´¸±μ° ±²¥É±μ° ¨ ¶μÎ±μ° μ¡Ê¸²μ¢²¥´μ ¤¢¨¦¥´¨¥³ (·¥É·μ£· ¤´μ¥ ¨ ´É¥·μ£· ¤´μ¥) ³¨ÉμÌμ´¤·¨° ¢¤μ²Ó ±É¨´μ¢ÒÌ ´¨É¥° ¨ § Ö±μ·¥¢ ´¨¥³
Î ¸É¨ μ·£ ´¥²² ¢ ¶·μɨ¢μ¶μ²μ¦´ÒÌ ¢¥·Ï¨´ Ì ¶μα¨ ¨ ³ É¥·¨´¸±μ° ±²¥É±¨.
ÉμÉ ¶·μÍ¥¸¸ ¸±μμ·¤¨´¨·μ¢ ´ ¸ ¶·μÌ즤¥´¨¥³ ±²¥Éμδμ£μ ͨ±² . „¥Ë¥±ÉÒ
¢ ´ ¸²¥¤μ¢ ´¨¨ ³¨ÉμÌμ´¤·¨° ¡²μ±¨·ÊÕÉ ¶·μÌ즤¥´¨¥ ±²¥Éμδμ£μ ͨ±² , ¨³¥´´μ ͨÉ챨´¥§. “ ³ÊÉ ´Éμ¢ ¸ ¤¥Ë¥±Éμ³ ´ ¸²¥¤μ¢ ´¨Ö ³¨ÉμÌμ´¤·¨°
(mdm10Δ ¨ mmr1Δ gem1Δ) ¢μ§´¨± ÕÉ ±²¥É±¨ ¸ ³´μ¦¥¸É¢¥´´Ò³¨ ¶μα ³¨ [206, 207]. ŒÊÉ ´É ¢¸Éʶ ¥É ¢ G2 ´ 20 ³¨´ ¶μ§¤´¥¥, Î¥³ ¤¨±¨° ɨ¶.
¡· §μ¢ ´¨¥ ¢Éμ·μ° ¶μα¨ ¶·μ¨¸Ìμ¤¨É Î¥·¥§ 150 ³¨´ ¶μ¸²¥ ¢Ò¸¢μ¡μ¦¤¥´¨Ö μÉ ·¥¸É ¢ G1 ¨ ¸¶Ê¸ÉÖ 25 ³¨´ ¶μ¸²¥ μ¡· §μ¢ ´¨Ö ¶¥·¢μ° ¶μα¨. ÉμÉ
Ë¥´μɨ¶ μ¡Ê¸²μ¢²¥´ ¤¥Ë¥±Éμ³ Í¨É챨´¥§ [207]. μ± § ´μ ÊÎ ¸É¨¥ MEN
¢ ͨÉ챨´¥§¥ ¨ Î¥±¶μ°´É¥ ´ ¸²¥¤μ¢ ´¨Ö ³¨ÉμÌμ´¤·¨°. ‚ ±²¥É± Ì mdm10Δ
´ ¡²Õ¤ ¥É¸Ö ¤¥Ë¥±É ¢Ò¸¢μ¡μ¦¤¥´¨Ö ¨§ Ö¤·Òϱ Í¥´É· ²Ó´μ£μ ¨£·μ± MEN
Ëμ¸Ë É §Ò Cdc14, ÎÉμ ¢²¨Ö¥É ´ ¥£μ ¸¶μ¸μ¡´μ¸ÉÓ ±É¨¢¨·μ¢ ÉÓ ¸Ê¡¸É· ÉÒ ¢
¶¥·¥Ï¥°±¥ ¶μα¨ ¨ SPB. ‚Ò¸± § ´μ ¶·¥¤¶μ²μ¦¥´¨¥ μ ¸ÊÐ¥¸É¢μ¢ ´¨¨ ¸¨¸É¥³Ò
±μ´É·μ²Ö, ±μÉμ· Ö ¨´£¨¡¨·Ê¥É ¸¦¨³ ´¨¥ ±μ²ÓÍ ³¥¦¤Ê ±²¥É±μ° ¨ ¶μαμ°,
¥¸²¨ ¨³¥ÕÉ¸Ö ¤¥Ë¥±ÉÒ ´ ¸²¥¤μ¢ ´¨Ö ³¨ÉμÌμ´¤·¨°. ˆ§¢¥¸É´μ, ÎÉμ ´¥±μÉμ·Ò¥
±μ³¶μ´¥´ÉÒ MEN ²μ± ²¨§μ¢ ´Ò ¢ ¸ °É¥ ¸¡μ·±¨ ±μ²ÓÍ [208Ä211]. „¥²¥Í¨Ö BUB2, £¨¶¥· ±É¨¢¨·ÊÕÐ Ö M…N, ¸Ê¶·¥¸¸¨·Ê¥É ´ ·ÊÏ¥´¨¥ ͨÉ챨´¥§ Ê
³ÊÉ ´Éμ¢ mdm10Δ ¨ mmr1Δ gem1Δ. “¸²μ¢¨Ö, ¶μ¤ ¢²ÖÕШ¥ ËÊ´±Í¨μ´¨·μ¢ ´¨¥ MEN ¶·¨ ¢ÒÌ줥 ¨§ ³¨Éμ§ (³ÊÉ Í¨¨, μ¸² ¡²ÖÕШ¥ ¢§ ¨³μ¤¥°¸É¢¨¥
Cdc14 ¸ ¨´£¨¡¨Éμ·μ³ Cˇ1/Net1, ¸¢¥·Ì¶·μ¤Ê±Í¨Ö ¨´£¨¡¨Éμ· SIC1 ±¨´ §Ò
CDK1 ¨²¨ ³ÊÉ Í¨¨, ¨´£¨¡¨·ÊÕШ¥ Ô±¸¶μ·É Cdc14 ¨§ Ö¤· ¢ ͨÉ춲 §³Ê)
¶·¨¢μ¤ÖÉ ± ¤¥Ë¥±É ³ ͨÉ챨´¥§ [208, 211Ä215]. MEN ³μ¦¥É ±μ´É·μ²¨·μ¢ ÉÓ
ͨÉ챨´¥§, ´ ¶· ¢²ÖÖ ¢μ¢²¥Î¥´´Ò¥ ¢ μ¡· §μ¢ ´¨¥ ¸¥¶ÉÒ ¡¥²±¨ ± ¶¥·¥Ï¥°±Ê
¶μα¨ [216Ä218].
Šμ´É·μ²¨·Ê¥É¸Ö ´¥ Éμ²Ó±μ ´ ¸²¥¤μ¢ ´¨¥ ³¨ÉμÌμ´¤·¨°, ´μ ¨ ¨Ì ± Î¥¸É¢μ.
Ò²μ ¶μ± § ´μ, ÎÉμ ³¨ÉμÌμ´¤·¨¨ ¸ ´¨§±¨³ ³¥³¡· ´´Ò³ ¶μÉ¥´Í¨ ²μ³ ¶·¥¤¶μÎɨɥ²Ó´μ μ¸É ÕÉ¸Ö ¢ ³ É¥·¨´¸±μ° ±²¥É±¥ [219]. Œ¥Ì ´¨§³ ´¥¨§¢¥¸É¥´,
´μ ÊΨÉÒ¢ Ö ¸¶μ¸μ¡ ¤¢¨¦¥´¨Ö ³¨ÉμÌμ´¤·¨° ¢ ¤μÎ¥·´ÕÕ ±²¥É±Ê, ¶·¥¤²μ¦¥´ ¸²¥¤ÊÕÐ Ö ³μ¤¥²Ó. „²Ö ´ ¶· ¢²¥´´μ£μ ´É¥·μ£· ¤´μ£μ ¤¢¨¦¥´¨Ö ³¨ÉμÌμ´¤·¨° ¢ ¶μÎ±Ê É·¥¡ÊÕÉ¸Ö ±É¨´μ¢Ò¥ ´¨É¨. Œ¨ÉμÌμ´¤·¨Ö, ±μÉμ· Ö ¤¢¨£ ¥É¸Ö ¨§
³ É¥·¨´¸±μ° ±²¥É±¨ ¢ ¶μαÊ, ¶²Ò¢¥É ¢¢¥·Ì ¶μ ɥΥ´¨Õ, ¶·¥μ¤μ²¥¢ Ö ¶·μɨ¢μ¶μ²μ¦´Ò° ·¥É·μ£· ¤´Ò° ¶μÉμ±. ·¥¤¶μ² £ ¥É¸Ö, ÎÉμ Éμ²Ó±μ ¢Ò¸μ±μ ËÊ´±Í¨μ´ ²Ó´Ò¥ ³¨ÉμÌμ´¤·¨¨, ±μÉμ·Ò¥ μ¡² ¤ ÕÉ ´É¥·μ£· ¤´μ° ¸¨²μ°, ¤μ¸É Éμδμ°
¤²Ö ¶·¥μ¤μ²¥´¨Ö ¶·μɨ¢μ¶μ²μ¦´μ£μ ·¥É·μ£· ¤´μ£μ ¶μÉμ± , ¡Ê¤ÊÉ ¶¥·¥¤ ¢ ÉÓ¸Ö
¨ ¸μÌ· ´ÖÉÓ¸Ö ¢ · §¢¨¢ ÕÐ¨Ì¸Ö ¤μÎ¥·´¨Ì ±²¥É± Ì ¢ ¶·μÍ¥¸¸¥ ´ ¸²¥¤μ¢ ´¨Ö.
25
± § ²μ¸Ó, ÎÉμ ±μ´É·μ²¨·Ê¥É¸Ö ´¥ Éμ²Ó±μ ´ ¸²¥¤μ¢ ´¨¥ ¨ ± Î¥¸É¢μ ³¨ÉμÌμ´¤·¨°, ´μ ¨ ±μ²¨Î¥¸É¢μ ³É„Š [220]. “É· É ³É„Š (´μ ´¥ ´ ·ÊÏ¥´¨¥
¤ÒÌ ´¨Ö) Ê rho0 -³ÊÉ ´Éμ¢ ¶·¨¢μ¤¨É ± ´ ·ÊÏ¥´¨Õ ¶·μÌ즤¥´¨Ö G1/S. μ¸²¥
¢Ò¸¢μ¡μ¦¤¥´¨Ö μÉ ·¥¸É ¢ G1 ±²¥É±¨ rho+ ¶·μÌμ¤ÖÉ G1/S Î¥·¥§ 40Ä60 ³¨´,
S/G2 Î¥·¥§ 100Ä120 ³¨´. ¤´ ±μ ¶μ²μ¢¨´ ±²¥Éμ± rho0 ´¥ ³μ£ÊÉ ¶·μ°É¨
G1/S, μ¸É ²Ó´Ò¥ ±²¥É±¨ rho0 ¤¥²ÖÉ¸Ö ¸ ´¨§±μ° ¸±μ·μ¸ÉÓÕ. ´¨ ¶·μÌμ¤ÖÉ
G1/S Î¥·¥§ 60Ä100 ³¨´, S/G2 Î¥·¥§ 150 ³¨´. ’ ±¨³ μ¡· §μ³, ÊÉ· É ³É„Š
¶·¨¢μ¤¨É ± ´ ·ÊÏ¥´¨Õ ¶·μÌ즤¥´¨Ö G1/S. „²Ö ÔÉμ° μ¸É ´μ¢±¨ ´¥μ¡Ì줨³ ±¨´ § Rad53.
ŒÉ„Š ¸¨´É¥§¨·Ê¥É¸Ö ´ ¶·μÉÖ¦¥´¨¨ ¢¸¥£μ ±²¥Éμδμ£μ ͨ±² , ¨ ¥¥ ±μ²¨Î¥¸É¢μ ±μ´É·μ²¨·Ê¥É¸Ö. Rad53 ·¥£Ê²¨·Ê¥É ±μ¶¨°´μ¸ÉÓ ³É„Š ¤¢Ê³Ö ¸¶μ¸μ¡ ³¨. ¥·¢Ò° ¶ÊÉÓ Å ¢²¨Ö´¨¥ ´ ¶Ê² ¤’” ¶μ¸·¥¤¸É¢μ³ ·¥£Ê²Öͨ¨ ±É¨¢´μ¸É¨ [3]. ¨§±¨° Ê·μ¢¥´Ó ±É¨¢´μ¸É¨ (¨²¨ ¤’”) ¶·¨¢μ¤¨É ±
¶μ¢ÒÏ¥´¨Õ ¶μÉ¥·¨ ³É„Š, ¢ Éμ ¢·¥³Ö ± ± ¢Ò¸μ±¨° Ê·μ¢¥´Ó ¤’” ¶μ´¨¦ ¥É
¶μÉ¥·Õ ³É„Š ¨ Ê¢¥²¨Î¨¢ ¥É ±μ¶¨°´μ¸ÉÓ ³É„Š [221Ä223]. ‚Éμ·μ° ¶ÊÉÓ Å
ÊÎ ¸É¨¥ Rad53 ¢ ¶¥·¥¤ Î¥ ¸¨£´ ² Î¥±¶μ°´É [222]. ”Ê´±Í¨Ö Î¥±¶μ°´É ¶μ¢·¥¦¤¥´¨° „Š ¢ ±μ´É·μ²¨·μ¢ ´¨¨ ±μ²¨Î¥¸É¢ ³É„Š ±μ´¸¥·¢ ɨ¢´ . ’ ±,
´¥°·μ¤¥£¥´¥· ɨ¢´μ¥ § ¡μ²¥¢ ´¨¥ É ±¸¨Ö-É¥²¥ ´£¨μﱃ §¨Ö, ¢Ò§¢ ´´μ¥ ³ÊÉ Í¨¥° ¢ £¥´¥ ¤·Ê£μ° Î¥±¶μ°´É´μ° ±¨´ §Ò ’Œ, Ì · ±É¥·¨§Ê¥É¸Ö ¸´¨¦¥´¨¥³
±μ¶¨°´μ¸É¨ ³É„Š ¢ ±²¥É± Ì ¶ ͨ¥´Éμ¢, É ±¦¥ Ê ³ÒÏ¥± ¶·¨ ´μ± ÊÉ¥ £¥´ ’Œ, ¨ ¢ ˨¡·μ¡² ¸É Ì, μ¡· ¡μÉ ´´ÒÌ ¨´£¨¡¨Éμ·μ³ ’Œ KU-55933 [224].
μ¸±μ²Ó±Ê ¨§³¥´¥´¨Ö ¸μ¤¥·¦ ´¨Ö ³É„Š ¸¢Ö§ ´Ò ¸μ ³´μ£¨³¨ Ëμ·³ ³¨ · ± ,
¢ · ±μ¢ÒÌ ±²¥É± Ì Î¥²μ¢¥± μ¡Òδμ μ¡´ ·Ê¦¨¢ ÕÉ ´ ·ÊÏ¥´¨Ö ¡¥²±μ¢ Î¥±¶μ°´É ¶μ¢·¥¦¤¥´¨° „Š, ¢μ§³μ¦´μ, ÎÉμ ¨§³¥´¥´¨Ö ¢ ³¥É ¡μ²¨§³¥ · ±μ¢ÒÌ
±²¥Éμ±, É ±¨¥ ± ± ÔËË¥±É ‚ ·¡Ê·£ (¶μ´¨¦¥´¨¥ ³¨ÉμÌμ´¤·¨ ²Ó´μ£μ ¤ÒÌ ´¨Ö
¨ ¶μ¢ÒÏ¥´¨¥ ´ Ô·μ¡´μ£μ £²¨±μ²¨§ ), ¢μ§´¨± ÕÉ ¢ ·¥§Ê²ÓÉ É¥ ¤¥·¥£Ê²Öͨ¨
Î¥±¶μ°´É ³É„Š.
·¥¤¶μ² £ ¥É¸Ö, ÎÉμ ÊÉ· É ³É„Š ±É¨¢¨·Ê¥É ±¨´ §Ê Rad53, ¨´¨£¨¡¨·ÊÕÐÊÕ ¶·μÌ즤¥´¨¥ G1/S. ‚²¨Ö´¨¥ Rad53 ´ G1-μ¸É ´μ¢±Ê Ê rho0 ´¥ ¸¢Ö§ ´μ ¸ ¢²¨Ö´¨¥³ ´ ¶Ê² ¤’”. Š ¸Ê¡¸É· É ³ Rad53 μÉ´μ¸¨É¸Ö £¥²¨± § Pif1,
Ëμ¸Ëμ·¨²¨·Ê¥³ Ö Ê rho0 -³ÊÉ ´Éμ¢. ƒ¥²¨± § Pif1 ËÊ´±Í¨μ´¨·Ê¥É ± ± ¢ Ö¤·¥,
É ± ¨ ¢ ³¨ÉμÌμ´¤·¨ÖÌ [225]. Ÿ¤¥·´ Ö Ëμ·³ Pif1 ÊÎ ¸É¢Ê¥É ¢ Ëμ·³¨·μ¢ ´¨¨
¨ ʤ²¨´¥´¨¨ É¥²μ³¥·, ·¥¶²¨± ͨ¨ ·¥±μ³¡¨´ ´É´ÒÌ ³μ²¥±Ê² „Š, ¸¨´É¥§¥
Ë· £³¥´Éμ¢ ± § ±¨, ¶·¥¤μÉ¢· Ð¥´¨¨ ·¥μ·£ ´¨§ ͨ¨ Ì·μ³μ¸μ³ ¨ ·¥¶ · ͨ¨
„Š. Ÿ¤¥·´Ò° ¶Ê² Pif1 ¶μ¤¢¥·£ ¥É¸Ö Ëμ¸Ëμ·¨²¨·μ¢ ´¨Õ ¶·¨ ±É¨¢ ͨ¨
Rad53 ¶μ¢·¥¦¤¥´¨Ö³¨ „Š [226]. Œ¨ÉμÌμ´¤·¨ ²Ó´Ò° ¶Ê² Pif1 ²μ± ²¨§μ¢ ´
¢ ´Ê±²¥μ¨¤ Ì ¨ ´¥μ¡Ì줨³ ¤²Ö ¶μ¤¤¥·¦ ´¨Ö ³É„Š. ʱ²¥μ¨¤ Ö¢²Ö¥É¸Ö ¥¤¨´¨Í¥° ´ ¸²¥¤μ¢ ´¨Ö ³É„Š ¨ ¶·¥¤¸É ¢²Ö¥É ¸μ¡μ° ´Ê±²¥μ¶·μÉ¥¨´μ¢Ò° ±μ³¶²¥±¸, · ¸¶μ²μ¦¥´´Ò° ¢ ³ É·¨±¸¥ ¨ ¢§ ¨³μ¤¥°¸É¢ÊÕШ° ¸ ¢´¥Ï´¥° ¨ ¢´ÊÉ·¥´´¥° ³¨ÉμÌμ´¤·¨ ²Ó´Ò³¨ ³¥³¡· ´ ³¨. „²Ö · ¢´μ³¥·´μ£μ · ¸¶·¥¤¥²¥´¨Ö
³¨ÉμÌμ´¤·¨° ´¥μ¡Ì줨³μ ¨Ì ¶· ¢¨²Ó´μ¥ ¢§ ¨³μ¤¥°¸É¢¨¥. ·¨±·¥¶²¥´¨¥ ´Ê±²¥μ¨¤ ± ³¥³¡· ´¥ ³¨ÉμÌμ´¤·¨° μ¡¥¸¶¥Î¨¢ ¥É ´ ¸²¥¤μ¢ ´¨¥ ³É„Š ¶·¨
26
¸¥£·¥£ ͨ¨ ³¨ÉμÌμ´¤·¨°. •μÉÖ ¢¸¥ ´Ê±²¥μ¨¤Ò ¸μ¤¥·¦ É ³É„Š ¨ ¡¥²μ± ʶ ±μ¢±¨ Abf2, Éμ²Ó±μ ±É¨¢´μ ·¥¶²¨Í¨·ÊÕШ¥¸Ö ´Ê±²¥μ¨¤Ò ¸μ¤¥·¦ É ¡¥²μ±
Mgm101, μ¶μ¸·¥¤ÊÕШ° ·¥±μ³¡¨´ Í¨Õ „Š ¨ ¸ÊÐ¥¸É¢¥´´Ò° ¤²Ö ¶μ¤¤¥·¦ ´¨Ö ³É„Š [227]. ÉμÉ ¡¥²μ± £μ³μ²μ£¨Î¥´ ±μ´¸¥·¢ ɨ¢´Ò³ ¡¥²± ³ ·¥±μ³¡¨´ ͨ¨, ´¥μ¡Ì줨³ ¤²Ö ·¥±μ³¡¨´ ͨ¨ ¶μ¢Éμ·μ¢ „Š ¨ ¤²Ö ·¥¶ · ͨ¨
챨¸²¨É¥²Ó´ÒÌ ¶μ¢·¥¦¤¥´¨° ³É„Š [227Ä229]. ‚ ´Ê±²¥μ¨¤ ¢Ìμ¤ÖÉ Ë¥·³¥´ÉÒ
É· ´¸±·¨¶Í¨¨, ·¥¶²¨± ͨ¨, ·¥¶ · ͨ¨ ¨ ·¥±μ³¡¨´ ͨ¨. “ rho− ±²¥Éμ±, ¨³¥ÕÐ¨Ì ´Ê±²¥μ¨¤Ò, ´¥ ´ ¡²Õ¤ ¥É¸Ö Î¥±¶μ°´É-μ¸É ´μ¢± . “ ±²¥Éμ± rho0 ´¥É
´Ê±²¥μ¨¤μ¢, ¨ Rad53 ± ±¨³-Éμ μ¡· §μ³ ÔÉμ μ¶·¥¤¥²Ö¥É. ‘±·¨´¨´£ £¥´μ³ ¶μ± § ² £¥´¥É¨Î¥¸±μ¥ ¢§ ¨³μ¤¥°¸É¢¨¥ RAD53 ¨ £¥´μ¢ ·¥¶ · ͨ¨ „Š, É ±¨Ì
± ± RAD6 ¨ RAD27, ¸ £¥´ ³¨ ¶μ¤¤¥·¦ ´¨Ö ³É„Š, ¢±²ÕÎ Ö MMM1, MMM2,
MDM10, MDM12, MDM32 [230]. ‚ÒÖ¢²¥´μ ¢²¨Ö´¨¥ CDK1 ´ ¸¥£·¥£ ͨÕ
³¨ÉμÌμ´¤·¨° [231].
‘¥£·¥£ ꬅ . ‘ÊÐ¥¸É¢Ê¥É Ö¤¥·´Ò° (Ö) ¨ ±μ·É¨± ²Ó´Ò° (±) Ô´¤μ¶² §³ ɨΥ¸±¨° ·¥É¨±Ê²Ê³. ¸²¥¤μ¢ ´¨¥ Ö μ¡Ê¸²μ¢²¥´μ ¥£μ ¸¢Ö§ÓÕ ¸
μ¡μ²μÎ±μ° Ö¤· , ¶μÔÉμ³Ê ¢ ¶·μÍ¥¸¸¥ ¤¥²¥´¨Ö ±²¥É±¨ Ö¤·μ É Ð¨É Ö § ¸μ¡μ°. ¸²¥¤μ¢ ´¨¥ ± Å ¡μ²¥¥ ¸²μ¦´Ò°, ³´μ£μ¸Éʶ¥´Î ÉÒ° ¶·μÍ¥¸¸, ±μÉμ·Ò° § ¢¨¸¨É μÉ ±É¨´μ¢μ£μ ͨÉμ¸±¥²¥É ¨ ·¥£Ê²¨·Ê¥É¸Ö ±²¥Éμδҳ ͨ±²μ³.
’·Ê¡±¨ ± ¤¢¨£ ÕÉ¸Ö ¢ ³ ²¥´Ó±ÊÕ ¶μÎ±Ê Myo4-§ ¢¨¸¨³Ò³ ¸¶μ¸μ¡μ³. ‚ ¢¥·Ï¨´¥ ¶μα¨ μ´¨ ¸´ Î ² § Ö± ·¨¢ ÕɸÖ, ¶μ§¤´¥¥ · ¸¶·¥¤¥²ÖÕÉ¸Ö ¢μ±·Ê£
¶μ ¶¥·¨Ë¥·¨¨ ¢¸¥° ¶μα¨. §·ÊÏ¥´¨¥ ¡¥²±μ¢ Sce1 ¨²¨ Ice2, μ¶μ¸·¥¤ÊÕШÌ
§ Ö±μ·¥¢ ´¨¥ ± ¢ ¢¥·Ï¨´¥ ¶μα¨, ¶·¨¢μ¤¨É ± ¤¥Ë¥±É ³ ±²¥ÉμÎ´μ° Ô²μ´£ ͨ¨, μ·£ ´¨§ ͨ¨ ¸¥¶É¨´μ¢ ¢ ¶¥·¥Ï¥°±¥ ¨ £¨¶¥· ±É¨¢ ͨ¨ Swe1 [232]. Swe1,
¨´£¨¡¨Éμ· ±¨´ §Ò CDK1, ·¥£Ê²¨·Ê¥É ¶·μÌ즤¥´¨¥ G2/M ¶μ¸·¥¤¸É¢μ³ ³μ·Ëμ²μ£¨Î¥¸±μ£μ Î¥±¶μ°´É . ‘¥¶É¨´Ò μ¡¥¸¶¥Î¨¢ ÕÉ ¶² ÉËμ·³Ê ¤²Ö § ±·¥¶²¥´¨Ö ¢
¶¥·¥Ï¥°±¥ ³´μ£μΨ¸²¥´´ÒÌ ¡¥²±μ¢, ¢μ¢²¥Î¥´´ÒÌ ¢ ¶·μÌ즤¥´¨¥ ±²¥Éμδμ£μ
ͨ±² , ¨ ¤μ¸É ¢± Swe1 ± ÔÉμ° ¶² ÉËμ·³¥ μ¶·¥¤¥²Ö¥É ¥¥ ¤¥£· ¤ Í¨Õ [233].
’ ±¨³ μ¡· §μ³, ´ ·ÊÏ¥´¨¥ ¸¡μ·±¨ ¸¥¶É¨´μ¢ ¢ ¶¥·¥Ï¥°±¥ ¶μα¨ ¢ ·¥§Ê²ÓÉ É¥ ¤¥Ë¥±É · ¸¶·¥¤¥²¥´¨Ö ± ¶·¥¶ÖÉ¸É¢Ê¥É ¶μ¤ ¢²¥´¨Õ Swe1 ¨ ¶·¨¢μ¤¨É
± ¥£μ £¨¶¥· ±É¨¢ ͨ¨, ±μÉμ· Ö § ¶Ê¸± ¥É ³μ·Ëμ²μ£¨Î¥¸±¨° Î¥±¶μ°´É ¢ G2/M.
ɸդ ¨ ʤ²¨´¥´´Ò° Ë¥´μɨ¶ ±²¥Éμ±, ´ ¡²Õ¤ ¥³Ò° ¶·¨ ´ ·ÊÏ¥´¨¨ ´ ¸²¥¤μ¢ ´¨Ö ±, ¶μ¸±μ²Ó±Ê ¶¥·¥±²ÕÎ¥´¨¥ μÉ ¶¨± ²Ó´μ£μ ± ¨§μÉ·μ¶´μ³Ê ·μ¸ÉÊ
¶μα¨ ¶·μ¨¸Ìμ¤¨É ¢ G2/M.
μαÊÕШ¥¸Ö ¤·μ¦¦¨ μ¡² ¤ ÕÉ ³¥Ì ´¨§³μ³ ±μ´É·μ²Ö ´ ¸²¥¤μ¢ ´¨Ö ±
¨ ·¥£Ê²Öͨ¥° ¶·μÌ즤¥´¨Ö ±²¥Éμδμ£μ ͨ±² ¢ μÉ¢¥É ´ ¥£μ ¤¥Ë¥±ÉÒ. ÉμÉ
¶ÊÉÓ § ³¥¤²Ö¥É ͨÉ챨´¥§, ¢¥·μÖÉ´μ, ¨§³¥´ÖÖ ¤¨´ ³¨±Ê ±μ³¶²¥±¸ ¸¥¶É¨´μ¢,
¨ ¨´£¨¡¨·Ê¥É ´ ¸²¥¤μ¢ ´¨¥ ± ¢ μÉ¢¥É ´ -¸É·¥¸¸. ‚ ·¥§Ê²ÓÉ É¥, ¢ ʸ²μ¢¨ÖÌ ¸É·¥¸¸ ¶·μ¨¸Ìμ¤¨É ¶·¥¨³ÊÐ¥¸É¢¥´´μ¥ · ¸¶μ²μ¦¥´¨¥ ± ¢ ³ É¥·¨´¸±μ° ±²¥É±¥ ¨ § ³¥¤²¥´¨¥ ͨÉ챨´¥§ ¤μ ¢μ¸¸É ´μ¢²¥´¨Ö ËÊ´±Í¨¨ . ·¨
ÔÉμ³ ±μ´É·μ²Ó ± Î¥¸É¢ ¢ ¶·μÍ¥¸¸¥ ´ ¸²¥¤μ¢ ´¨Ö ¢²¨Ö¥É ´ ¦¨§´¥¸¶μ¸μ¡´μ¸ÉÓ ±²¥Éμ±. ŒÊÉ Í¨¨, ±μÉμ·Ò¥ ¶μ¤ ¢²ÖÕÉ ÔÉμÉ Î¥±¶μ°´É ¨ ¶μ§¢μ²ÖÕÉ
´ ¸²¥¤μ¢ ÉÓ ±μ³¶·μ³¨¸¸´Ò° , ¸´¨¦ ÕÉ ¶·μ¤μ²¦¨É¥²Ó´μ¸ÉÓ ¦¨§´¨ [234].
27
— ¸ÉÓ Cdc28 É¥¸´μ ¸Í¥¶²¥´ ¸ ³ É·¨±¸μ³ ͨÉμ¸±¥²¥É [235] ¨ [236].
±É¨´μ¢Ò° ͨÉμ¸±¥²¥É ¨ ¢ ´¥±μÉμ·μ° ¸É¥¶¥´¨ ±μ²μ± ²¨§μ¢ ´Ò, ¨ ¤¨´ ³¨± § ¢¨¸¨É μÉ Í¨Éμ¸±¥²¥É [237]. μ¤¢¨¦´μ¸ÉÓ ¨ ¸É·Ê±ÉÊ· ³¨ÉμÌμ´¤·¨° É ±¦¥ § ¢¨¸ÖÉ μÉ Í¨Éμ¸±¥²¥É [238] ¨ ³μ£ÊÉ ¢²¨ÖÉÓ ´ ¨§³¥´¥´¨Ö ¢
¸É·Ê±ÉÊ·¥ [239]. Cdc28 ¨ Cln3 ¸¢Ö§Ò¢ ÕÉ¸Ö ¸ ¢ ³¥¸É Ì, ±μ´É ±É¨·ÊÕÐ¨Ì ¸ ͨÉμ¸±¥²¥Éμ³, ÎÉμ, ¢¥·μÖÉ´μ, ¸¶μ¸μ¡¸É¢Ê¥É ÊÎ ¸É¨Õ ±¨´ §Ò CDK1 ¢
³μ·Ëμ£¥´¥§¥, ´ ¶·¨³¥·, ¡¨μ£¥´¥§¥ ¢ ±Êμ²¥° ¨ ³¨ÉμÌμ´¤·¨°. „¥°¸É¢¨É¥²Ó´μ,
¸Ê¡¸É· Éμ³ ±¨´ §Ò Ö¢²Ö¥É¸Ö ¡¥²μ± Bem1. ¥²±¨ Bem1, Cdc24, Cdc42 ²μ± ²¨§μ¢ ´Ò ¢ ¸ °É¥ ¶μÎ±μ¢ ´¨Ö ¨ ·¥μ·£ ´¨§ÊÕÉ ±É¨´μ¢Ò° ͨÉμ¸±¥²¥É ¤²Ö
Ê¸É ´μ¢²¥´¨Ö ¶μ²Ö·¨§ ͨ¨ [240]. Cdc28/Cln3 ·¥£Ê²¨·Ê¥É ¡¨μ£¥´¥§ ¢ ±Êμ²¥°
Bem1-§ ¢¨¸¨³Ò³ ¶ÊÉ¥³ [241]. ’ ±¨³ μ¡· §μ³, ´ ¸²¥¤μ¢ ´¨¥ μ·£ ´¥²², É ±¨Ì
± ± ¶¥·μ±¸¨¸μ³Ò ¨ ¢ ±Ê첨, ¨ ¤·Ê£¨Ì ±μ³¶μ´¥´É ¸¥±·¥Éμ·´μ£μ ¶Êɨ ·¥£Ê²¨·Ê¥É¸Ö ¡¥²± ³¨, ±μÉμ·Ò¥ ±μ´É·μ²¨·ÊÕÉ ¶·μÌ즤¥´¨¥ ±²¥Éμδμ£μ ͨ±² .
μ-¢¨¤¨³μ³Ê, ¸ÊÐ¥¸É¢ÊÕÉ ¶μ± ³ ²μ¨§ÊÎ¥´´Ò¥ Î¥±¶μ°´ÉÒ ¤²Ö ´ ¸²¥¤μ¢ ´¨Ö
μ·£ ´¥²², ±μÉμ·Ò¥ μ¡· §ÊÕÉ¸Ö de novo.
¢Éμ· ¶·¨´μ¸¨É ¡² £μ¤ ·´μ¸ÉÓ . ˆ. †Êα¨´μ° § ¶μ³μÐÓ ¢ ¨§£μÉμ¢²¥´¨¨
·¨¸Ê´± .
‹ˆ’…’“
1. Mills, K. D., Sinclar, D. A., and Guarente, L. (1997) Cell, 97, 609Ä620.
2. Ritchie, K. B., Mallory, J. C., and Petes, T. D. (1999) Mol. Cell. Biol., 19, 6065Ä6075.
3. Elledge, S. J. (1996) Science, 274, 1664Ä1672.
4. Roos, W. P., and Kaina, B. (2006) Trends Mol. Med., 12, 440Ä450.
5. Šμ²Éμ¢ Ö, . . (2009) ƒ¥´¥É¨± , 45, 5Ä21.
6. Demeter, J., Lee, S. E., Harber, J. E., and Stearns, T. (2000) Mol. Cell, 6, 487Ä492.
7. Šμ²Éμ¢ Ö, . . (2013) ƒ¥´¥É¨± , 49, 797Ä813.
8. Garvik, B., Carson, M., and Hartwell, L. (1995) Mol. Cell. Biol., 15, 6128Ä6138.
9. Lee, S. E., Moore, J. K., Holmes, A., et al. (1998) Cell, 94, 399Ä409.
10. Giannattasio, M., Lazzaro, F., Longhese, M. P., et al. (2004) EMBO J., 23, 429Ä438.
11. Ivanov, E. L., Sugawara, N., White, C. I., et al. (1994) Mol. Cell. Biol., 14, 3414Ä
3425.
12. Tsubouchi, H., and Ogawa, H. (1998) Mol. Cell. Biol., 18, 260Ä268.
13. Putnam, C. D., Jaehning, E. J., and Kolodner, R. D. (2009) DNA Repair (Amst.), 8,
974Ä982.
14. Majka, J., Binz, S., Wold, M., and Burgers, P. (2006) J. Biol. Chem., 281, 27855Ä
27861.
15. Paciotti, V., Clerici, M., Lucchini, G., and Longhese, M. (2000) Genes Dev., 14,
2046Ä2059.
28
16. Rouse, J., and Jackson, S. P. (2002) Mol. Cell, 9, 857Ä869.
17. Lee, J. H., and Paull, T. T. (2005) Science, 308, 551Ä554.
18. Bakkenist, C. J., and Kastan, M. B. (2003) Nature, 421, 499Ä506.
19. Majka, J., Niedziela-Majka, A., and Burgers, P. M. (2006) Mol. Cell, 24, 891Ä901.
20. Navadgi-Patil, V. M., and Burgers, P. M. (2008) J. Biol. Chem., 283, 35853Ä35859.
21. Navadgi-Pati, V. M., and Burgers, P. M. (2009) Mol. Cell, 36, 743Ä753.
22. Puddu, F., Granata, M., Di Nola, L., et al. (2008) Mol. Cell. Biol., 28, 4782Ä4793.
23. Pfander, B., and Dif
ey, J. F. X. (2011) EMBO J., 30, 4897Ä4907.
24. Huyen, Y., Zgheib, O., Ditullio, R. A., et al. (2004) Nature, 432, 406Ä411.
25. Toh, G., O'Shaughnessy, A. M., Jimeno, S., et al. (2006) DNA Repair (Amst.), 5,
693Ä703.
26. Downs, J. A., Lowndes, N. F., and Jackson, S. P. (2000) Nature, 408, 1001Ä1004.
27. Brush, G. S., and Kelly, T. J. (2000) Nucleic. Acids Res., 28, 3725Ä3732.
28. Shroff, R., Arbel-Eden, A., Pilch, D., et al. (2004) Curr. Biol., 14, 1703Ä1711.
29. Celeste, A., Fernandez-Capetillo, O., Kruhlak, M., et al. (2003) Nat. Cell Biol., 5,
675Ä679.
30. Ward, I. M., Minn, K., Jorda, K. G., and Chen, J. (2003) J. Biol. Chem., 278, 19579Ä
19582.
31. Conde, F., Refolio, E., Cordon-Preciado, V., et al. (2009) Genetics, 182, 437Ä446.
32. Botuyan, M. V., Lee, J., Ward, I. M., et al. (2006) Cell, 127, 1361Ä1373.
33. Javaheri, A., Wysocki, R., Jobin-Robitaille, O., et al. (2006) Proc. Natl. Acad. Sci.
USA, 103, 13771Ä13776.
34. Gilbert, C. S., Bosch, Mv. M., Green, C. M., et al. (2003) EMBO Rep., 4, 953Ä958.
35. Gilbert, C. S., Green, C. M., and Lowndes, N. F. (2001) Mol. Cell, 8, 129Ä136.
36. Pellicioli, A., and Foiani, M. (2005) Curr. Biol., 15, R769Ä771.
37. Sun, Z., Hsiao, J., Fay, D. S., and Stem, D. F. (1998) Science, 281, 272Ä274.
38. Schwartz, M. F., Duong, J. K., Sun, Z., et al. (2002) Mol. Cell, 9, 1055Ä1065.
39. Sweeney, F. D., Yang, F., Chi, A., et al. (2005) Curr. Biol., 15, 1364Ä1375.
40. Usui, T., Foster, S. S., and Petrini, J. H. (2009) Mol. Cell, 33, 147Ä159.
41. Ubersax, J. A., and Ferrell, J. E. Jr. (2007) Nat. Rev. Mol. Cell. Biol., 8, 530Ä541.
42. Leroy, C., Lee, S. E., Vaze, M. B., et al. (2003) Mol. Cell, 11, 827Ä835.
43. Gunjan, A., and Verreault, A. (2003) Cell, 115, 537Ä549.
44. Sanchez, Y., Desany, B. A., Jones, W. J., et al. (1996) Science, 271, 357Ä360.
45. Paciotti, V., Clerici, M., Scotti, M., et al. (2001) Mol. Cell. Biol., 21, 3913Ä3925.
46. Mordes, D. A., and Cortez, D. (2008) Cell Cycle, 7, 2809Ä2812.
47. Giannattasio, M., Sommariva, E., Vercillo, R., et al. (2002) Proc. Natl. Acad. Sci.
USA, 99, 12997Ä13002.
29
48. Mantiero, D., Clerici, M., Lucchini, G., and Longhese, M. P. (2007) EMBO J., 8,
380Ä387.
49. Baldo, V., Testoni, V., Lucchini, G., and Longhese, M. (2008) Mol. Cell. Biol., 28,
358Ä375.
50. Nakada, D., Shimomura, T., Matsumoto, K., and Sugimoto, K. (2003) Nucleic Acids
Res., 31, 1715Ä1724.
51. Van den Bosch, M., and Lowndes, N. F. (2004) Cell Cycle, 3, 119Ä122.
52. Toh, G. W., and Lowndes, N. F. (2003) Biochem. Soc. Transact., 31, 242Ä246.
53. Smolka, M., Albuquerque, C., Chan, S. H., et al. (2005) Mol. Cell. Proteomics, 4,
1358Ä1369.
54. Tourriere, H., and Pasero, P. (2007) DNA Repair (Amst.), 6, 900Ä913.
55. Cobb, J. A., Bjergbaek, L., and Gasser, S. M. (2002) FEBS Lett., 529, 43Ä48
56. Frei, C., and Gasser, S. M. (2000) J. Cell Sci., 113, 2641Ä2646.
57. Hoege, C., Pfander, B., Moldovan, G. L., et al. (2002) Nature, 419, 135Ä141.
58. Bando, M., Katou, Y., Komata, M., et al. (2009) J. Biol. Chem., 284, 34355Ä34365.
59. Gambus, A., Jones, R. C., Sanchez-Diaz, A., et al. (2006) Nat. Cell Biol., 8, 358Ä366.
60. Alcasabas, A. A., Osborn, A. J., Bachant, J., et al. (2001) Nat. Cell Biol., 3, 958Ä965.
61. Osborn, A. J., and Elledge, S. J. (2003) Genes Dev., 17, 1755Ä1767.
62. Mohanty, B., Bairwa, N., and Bastia, D. (2006) Proc. Natl. Acad. Sci. USA, 103,
879Ä902.
63. Katou, Y., Kanoh, Y., Bando, M., et al. (2003) Nature, 424, 1078Ä1083.
64. Wang, H., and Elledge, S. J. (2002) Genetics, 160, 1295Ä1304.
65. Puddu, F., Piergiovanni, G., Plevani, P., and Muzi-Falconi, M. (2011) PLoS Genet.,
7, e1002022.
66. Lou, H., Komata, M., Katou, Y., et al. (2008) Mol. Cell, 32, 106Ä117.
67. Gottifredi, V., and Prives, C. (2005) Semin. Cell Dev. Biol., 16, 355Ä368.
68. De Antoni, A., and Gallwitz, D. (2000) Gene, 246, 179Ä185.
69. Hori, Y., Shirahige, K., Obuse, C., et al. (1996) Mol. Biol. Cell, 7, 409Ä418.
70. Berens, T. J., and Toczyski, D. P. (2012) Mol. Biol. Cell, 23, 1058Ä1067.
71. Komata, M., Bando, M., Araki, H., Shirahige, K. (2009) Mol. Cell. Biol., 29,
5008Ä5019.
72. Cotta-Ramusino, C., Fachinetti, D., Lucca, C., et al. (2005) Mol. Cell, 17, 153Ä159.
73. Redon, C., Pilch, D. R., and Bonner, W. M. (2006) Genetics, 172, 67Ä76.
74. Unal, E., Arbel-Eden, A., Sattler, U., et al. (2004) Mol. Cell, 16, 991Ä1002.
75. Marini, F., Pellicioli, A., Paciotti, V., et al. (1997) EMBO J., 16, 639Ä650.
76. Dotiwala, F., Haase, J., Arbel-Eden, A., et al. (2007) Proc. Natl. Acad. Sci. USA, 107,
11358Ä11363.
77. Šμ·μ²¥¢, ‚. ƒ. (2007) ¤¨ Í. ¨μ². ¤¨μÔ±μ²., 47, 389Ä401.
30
78. Lisby, M., Rothstein, R., and Mortensen, U. (2001) Proc. Natl. Acad. Sci. USA, 98,
8276Ä8282.
79. Antunez de Mayolo, A., Lisby, M., Erdeniz, N. et al. (2006) Nucleic Acids Res., 34,
2587Ä2597.
80. Ubersax, J. A., Woodbury, E. L., Quanh, P. N., et al. (2003) Nature, 425, 859Ä864.
81. Din, S., Brill, S. J., Fairman, M. P., and Stillman, B. (1990) Genes Dev., 4, 968Ä977.
82. Kim, H. S., and Brill, S. J. (2003) DNA repair (Amst.), 2, 1321Ä1335.
83. Ira, G., Pellicioli, A., Balijja, A., et al. (2004) Nature, 431, 1011Ä1017.
84. Pellicioli, A., Lee, S. E., Lucca, C., et al. (2001) Mol. Cell, 7, 293Ä300.
85. Clerici, M., Baldo, V., Mantiero, D., et al. (2004) Mol. Cell Biol., 24, 10126Ä10144.
86. Jazayeri, A., Falck, J., Lukas, C., et al. (2006) Nat. Cell Biol., 8, 37Ä45.
87. Huertas, P., Cortes-Ledesma, F., Sartori, A. A., et al. (2008) Nature, 455, 689Ä692.
88. Kosugi, S., Hasebe, M., Tomita, M., and Yanagawa, H. (2009) Proc. Natl. Acad. Sci.
USA, 106, 10171Ä10176.
89. Melo, J. A., Cohen, J., and Toczyski, D. P. (2001) Genes Dev., 15, 2809Ä2821.
90. Kondo, T., Wakayama, T., Naiki, T., et al. (2001) Science, 294, 867Ä870.
91. Zou, L., Cortez, D., and Elledge, S. J. (2002) Genes Dev., 16, 198Ä208.
92. Lisby, M., Barlow, J. H., Burgess, R. C., and Rothstein, R. (2004) Cell, 118, 699Ä713.
93. Bonilla, C. Y., Melo, J. A., and Toczyski, D. P. (2008) Mol. Cell, 30, 267Ä276.
94. Barlow, J. H., Lisby, M., and Rothstein, R. (2008) Mol. Cell, 30, 73Ä85.
95. Šμ²Éμ¢ Ö, ., ¨±Ê²Êϱ¨´ , ., Š ¤ÒÏ¥¢¸± Ö, …., ¨ ¤·. (2008) ƒ¥´¥É¨± , 44,
1045Ä1055.
96. Moses, A. M., Heriche, J. K., and Durbin, R. (2007) Genome Biol., 8, R23.
97. Albuquerque, C., Smolka, M., Payne, S., et al. (2008) Mol. Cell Proteomics, 7,
1389Ä1396.
98. Holt, I. J., Tuch, B. B., Johnson, A. D., et al. (2009) Science, 325, 1682Ä1686.
99. Emili, A. (1998) Mol. Cell, 2, 183Ä189.
100. Caspari, T., Murray, J. M., and Carr, A. M. (2002) Genes Dev., 16, 1195Ä1208.
101. Du, L. L., Nakamura, T. M., and Russell, P. (2006) Genes Dev., 20, 1583Ä1596.
102. Esashi, F., and Yanagida, M. (1999) Mol. Cell, 4, 167Ä174.
103. Pfander, B., and Dif
ey, J. F. (2011) EMBO J., 30, 4897Ä4907.
104. Granata, M., Lazzaro, F., Novarina, D., et al. (2010) PLoS Genet., 6, e1001047.
105. Blankley, R. T., and Lydall, D. (2004) J. Cell Sci., 117, 601Ä608.
106. Sanchez, Y., Bachant, J., Wang, H., et al. (1999) Science, 286, 1166Ä1171.
107. Gardner, R., Putman, C. W., and Weinert, T. (1999) EMBO J., 18, 3173Ä3185.
108. O'Shaughnessy, A. M., Grenon, M., Gilbert, C. et al. (2006) Methods Enzymol., 409,
131Ä150.
31
109. Vialard, J., Gilbert, C., Green, C., and Lowndes, N. (1998) EMBO J., 17, 5679Ä5688.
110. Grenon, M., Gilbert, C., and Lowndes, N. F. (2001) Nat. Cell Biol., 3, 844Ä847.
111. Greenon, M., Costelloe, T., Jimeno, S., et al. (2007) Yeast, 24, 105Ä119.
112. Smits, V. A. (2006) Cell Cycle, 5, 1039Ä1043.
113. Goto, H., Kariya, R., Shimamoto, M., et al. (2012) Cancer Sci., 103, 775Ä781.
114. Tapia-Alveal, C., Calonge, T. M., and O'Connell, M. J. (2009) Cell Div., 4, 8.
115. Abreu, C. M., Kumar, R., Hamilton, D., et al. (2013) PLOS Genet., 9(4), e1003310.
116. Hammet, A., Magill, C., Heierhorst, J., and Jackson, S. (2007) EMBO J., 8, 851Ä857.
117. Wysocki, R., Javaheri, A., Allard, S., et al. (2005) Mol. Cell Biol., 25, 8430Ä8443.
118. Chen, Y., Caldwell, J. M., Pereira, E., et al. (2009) J. Biol. Chem., 284, 182Ä190.
119. Gurley, L., Valdez, J. G., and Buchanan, J. S. (1995) J. Biol. Chem., 290, 27653Ä
27660.
120. Swaney, D., Beltrao, P., Starita, L., et al. (2013) Nat. Methods, 10,
doi:10. 1038/nmeth. 2519.
121. Alexandrow, M. G., and Hamlin, J. L. (2005) J. Cell Biol., 168, 875Ä886.
122. Yu, Q., Kuzmiak, H., Zou, Y., et al. (2009) J. Biol. Chem., 284, 740Ä750.
123. Downs, J., Kosmidou, E., Morgan, A., Jackson, S. P. (2003) Mol. Cell, 11,
1685Ä1692.
124. Georgieva, M., Roguev, A., Balashev, K., et al. (2012) Biochem. Biophys. Acta,
1819, 366Ä374.
125. Georgieva, M., Staneva, D., Uzunova, K., et al. (2015) Inter. J. Biochem. Cell Biol.,
59, 182Ä192.
126. Neves-Costa, A., Will, W. R., Vetter, A. T., et al. (2009) PLoS One, 4, e8111.
127. Awad, S., Ryan, D., Prochasson, P., et al. (2010) J. Biol. Chem., 285, 9477Ä9484.
128. Lo, W. S., Duggan, L., Emre, N. C., et al. (2001) Science, 293, 1142Ä1146.
129. Clements, A., Poux, A. N., Lo, W. S., et al. (2003) Mol. Cell, 12, 461Ä473.
130. Koltovaya, N., Guerasimova, A. S., Tchekhouta, I. A., et al. (2003) Yeast, 20,
955Ä971.
131. John, S., Howe, L., Tafrov, S. T., et al. (2000) Genes Dev., 14, 1196Ä1208.
132. Š ¤ÒÏ¥¢¸± Ö, …. ., Šμ²Éμ¢ Ö, . . (2009) ƒ¥´¥É¨± , 45, 458Ä470.
133. Li, X., and Cai, M. (1997) Mol. Cell Biol., 17, 2723Ä2734.
134. Sidorova, J. M., and Breeden, L. L. (1997) Genes Dev., 11, 3032Ä3045.
135. Sidorova, J. M., and Breeden, L. L. (2003) Mol. Cell. Biol., 23, 3405Ä3416.
136. •μ²³Ê·μ¤μ¢, •. ’., Šμ²Éμ¢ Ö, . . (2009) ¨μ˨§¨± , 54, 999Ä1004.
137. Allen, J. B., Zhou, Z., Siede, W., et al. (1994) Genes Dev., 8, 2401Ä2415.
138. Enserink, J., Hombaur, H., Huang, M., and Kolodner, R. (2009) J. Cell Biol., 185,
423Ä437.
139. Sorger, P. K., and Murray, A. W. (1992) Nature, 355, 365Ä368.
32
140. Kitazono, A. A., and Kron, S. J. (2002) J. Biol. Chem., 277, 48627Ä48634.
141. Santocanale, C., Dif
ey, J. F. X. (1998) Nature, 395, 615Ä618.
142. Zegerman, P., and Dif
ey, J. F. (2009) DNA Repair (Amst.), 8, 1077Ä1088.
143. Cheng, L., Collyer, T., and Hardy, C. F. (1999) Mol. Cell. Biol., 19, 4270Ä4278.
144. Dohrmann, P., Oshiro, G., Tecklenburg, M., and Sclafani, R. (1999) Genetics, 151,
965Ä977.
145. Pasero, P., Duncker, B., Schwob, E., and Gasser, S. (1999) Genes Dev., 13,
2159Ä2176.
146. Weinreich, M., and Stillman, B. (1999) EMBO J., 18, 5334Ä5346.
147. Vodenicharov, M. D., and Weillinger, R. J. (2006) Mol. Cell, 24, 127Ä137.
148. Miyake, Y., Nakamura, M., Nabetani, A., et al. (2009) Mol. Cell, 36, 193Ä206.
149. Surovtseva, Y. V., Churikov, D., Boltz, K. A., et al. (2009) Mol. Cell, 36, 207Ä218.
150. Gao, H., Cervantes, R., Mandell, E., et al. (2007) Nat. Struct. Mol. Biol., 14,
208Ä214.
151. Frank-Vaillant, M., and Marcand, S. (2002) Mol. Cell, 10, 1189Ä1199.
152. Aylon, Y., Liefshitz, B., and Kupiec, M. (2004) EMBO J., 23, 4868Ä4875.
153. Dewar, J. M., and Lydall, D. (2012) Chromosoma, 121, 117Ä130.
154. Jia, X., Weinert, T., and Lydall, D. (2004) Genetics, 166, 753Ä764.
155. Lydall, D., and Weinert, T. (1995) Science, 270, 1488Ä1491.
156. Nakada, D., Matsumoto, K., and Sugimoto, K. (2003) Genes Dev., 17, 1957Ä1962.
157. Usui, T., Ogawa, H., and Petrini, J. H. (2001) Mol. Cell, 7, 1255Ä1266.
158. Palou, G., Palou, R., Guerra-Moreno, A., et al. (2010) J. Biol. Chem., 285, 26431Ä
26440.
159. Geymonat, M., Spamos, A., Wells, G. P., et al. (2004) Mol. Cell. Biol., 24,
2277Ä2285.
160. Costanzo, M., Nishikawa, J. L., Tang, X., et al. (2004) Cell, 117, 899Ä913.
161. De Bruin, R., McDonald, W. H., Kalashnikova, T. I., et al. (2004) Cell, 117,
887Ä898.
162. De Bruin, R. A., Kalashnikova, T. I., Chahwan, C., et al. (2006) Mol. Cell, 23,
483Ä496.
163. De Bruin, R. A., and Wittenberg, C. (2009) Cell Cycle, 8, 214Ä217.
164. Huang, M., Zhou, Z., and Elledge, S. J. (1998) Cell, 94, 595Ä605.
165. Fu, Y., Pastushok, L., and Xiao, W. (2008) FEMS Microbiol. Rev., 32, 908Ä926.
166. Elledge, S. J., Zhou, Z., Allen, J. B., and Navas, T. A. (1993) Bioessay, 15, 333Ä339.
167. Zhao, X., Chabes, A., Domkin, V., et al. (2001) EMBO J., 20, 3544Ä3553.
168. Lee, Y. D., and Elledge, S. J. (2006) Genes Dev., 20, 334Ä344.
169. Liberi, G., Chiolo, I., Pelliciolli, A., et al. (2000) EMBO J., 19, 5027Ä5038.
170. Zierhut, C., and Dif
ey, J. F. (2008) EMBO J., 27, 1875Ä1885.
33
171. Sanchez, Y., Bachant, J., Price, C., et al. (1999) Science, 286, 1166Ä1171.
172. Agarwal, R., and Cohen-Fix, O. (2002) Genes Dev., 16, 1371Ä1382.
173. Agarwal, R., Tang, Z., Yu, H., and Cohen-Fix, O. (2003) J. Biol. Chem., 278,
45027Ä45033.
174. Hsu, W. S., Erickson, S. L., Tsai, H. J., et al. (2011) Mol. Cell. Biol., 31, 2470Ä2483.
175. Sandell, L. L, and Zakian, V. A. (1993) Cell, 75, 729Ä739.
176. Toczyski, D. P., Galgoczy, D. J., and Hartwell, L. H. (1997) Cell, 90, 1097Ä1106.
177. Lee, S., Pellicioli, A., Demeter, J., et al. (2000) Cold Spring Harbor Symp. Quant.
Biol., 65, 303Ä314.
178. O'Neill, B., Szyjka, S., Lis, E., et al. (2007) Proc. Natl. Acad. Sci. USA, 104,
9290Ä9295.
179. Cheng, L., Hunke, L., and Hardy, C. F. (1998) Mol. Cell. Biol., 18, 360Ä370.
180. Schleker, T., Shimada, K., Sack, R., et al. (2010) Cell Cycle, 9, 350Ä363.
181. Diani, L., Colombelli, C., Nachimuthu, B., et al. (2009) J. Biol. Chem., 284, 32627Ä
32634.
182. Shimada, K., Pasero, P., and Gasser, S. M. (2002) Genes Dev., 16, 3236Ä3252.
183. Tercero, J. A., Longhese, M. P., and Dif
ey, J. F. (2003) Mol. Cell, 11, 1323Ä1336.
184. McCusker,
845Ä851.
D.,
and Kellogg,
D. R. (2012) Curr. Opin. Cell Biol.,
24,
185. Barbet, N. C., and Carr, A. M. (1993) Nature, 364, 824Ä827.
186. Rowley, R., Hudson, J., and Young, P. G. (1992) Nature, 356, 353Ä355.
187. Amon, A., Surana, U., Muroff, I., and Nasmyth, K. (1992) Nature, 355, 368Ä371.
188. Barral, Y., Parra, M., Bidlingmaier, S., and Snyder, M. (1999) Genes Dev., 13,
176Ä187.
189. Barral, Y., Mermall, V., Mooseker, M., and Snyder, M. (2000) Mol. Cell, 5, 841Ä
851.
190. Bashirullah, A., Cooperstock, R., and Lipshitz, H. (1998) Annu. Rev. Biochem., 67,
335Ä394.
191. Takizawa, P., DeRisi, J. L., Withelm, J. E., and Vale, R. D. (2000) Science, 20,
341Ä344.
192. Longtine, M., Theesfeld, C. L., McMillan, J. N., et al. (2000) Mol. Cell, 20,
4049Ä4061.
193. Cid, V., Shulewitz, M., McDonald, K., and Thorner, J. (2001) Mol. Biol. Cell, 12,
1645Ä1669.
194. Longtine, M. S., Fares, H., and Pringle, J. R. (1998) J. Cell Biol., 143, 719Ä736.
195. McMillan, J., Longtine, M. S., Sia, R. A., et al. (1999) Mol. Cell. Biol., 19, 6929Ä
6939.
196. Shulewitz, M. J., Inouye, C. J., and Thorner, J. (1999) Mol. Cell. Biol., 19,
7123Ä7137.
34
197. Hanrahm, J., and Snyder, M. (2003) Mol. Cell, 12, 663Ä673.
198. Okizaki, D., and Nojima, H. (2001) FEBS Lett., 489, 197Ä201.
199. Lew, D. J., and Burke, D. J. (2003) Annu. Rev. Genet., 37, 251Ä282.
200. Chen, Y., and Sanchez, Y. (2004) DNA Repair (Amst.), 3, 1025Ä1032.
201. Suzuki, M., Igarashi, R., Sekiya, M., et al. (2004) Nat. Cell Biol., 6, 861Ä871.
202. De Bettignies, G., and Johnston, L. H. (2003) Curr. Biol., 13, R301.
203. Smeets, M. F., and Segal, M. (2002) Cell Cycle, 1, 308Ä311.
204. Jensen, S., Segal, M., Clarke, D. J., and Reed, S. I. (2001) J. Cell Biol., 152, 27Ä40.
205. Queralt, E., Lehane, C., Novak, B., and Uhimann, F. (2006) Cell, 125, 719Ä732.
206. Sogo, L. F., and Yaffe, M. P. (1994) J. Cell Biol., 126, 1361Ä1373.
207. Garcia-Rodriguez, L., Crider, D., Gay, A., et al. (2009) Curr. Biol., 19, 1730Ä1735.
208. Song, S., Grenfell, T. Z., Garˇeld, S., et al. (2000) Mol. Cell. Biol., 20, 286Ä298.
209. Xu, S., Huang, H. K., Kaiser, P., et al. (2000) Curr. Biol., 10, 329Ä332.
210. Yoshida, S., and Toh-e, A. (2001) Genes Genet. Syst., 76, 141Ä147.
211. Bembenek, J., Kang, J., Kurischko, C., et al. (2005) Cell Cycle, 4, 961Ä971.
212. Jimenez, J., Cid, V. J., Cenamor, R., et al. (1998) J. Cell Biol., 143, 1617Ä1634.
213. Shou, W., Seol, J. H., Shevchenko, A., et al. (1999) Cell, 97, 233Ä244.
214. Lippincott, J., Shannon, K. B., Shou, W., et al. (2001) J. Cell Sci., 114, 1379Ä1386.
215. Hwa Lim, H., Yeong, F. M., and Surana, U. (2003) Mol. Biol. Cell, 14, 4734Ä4743.
216. Blondel, M., Bach, S., Bamps, S., et al. (2005) EMBO J., 24, 1440Ä1452.
217. Meitinger, F., Petrova, B., Lombardi, I. M., et al. (2010) J. Cell Sci., 123, 1851Ä1861.
218. Nishihama, R., Schreiter, J. H., Onishi, M., et al. (2009) J. Cell Biol., 185, 995Ä1012.
219. Lai, C. Y., Jaruga, E., Borghouts, C., and Jazwinski, S. M. (2002) Genetics, 162,
73Ä87.
220. Crider, D., Garcia-Rodrigues, L., Srivastava, P., et al. (2012) J. Cell Biol., 198,
793Ä798.
221. Tayloer, S. D., Zhang, J. S., Eaton, M. S., et al. (2005) Mol. Biol. Cell, 16,
3010Ä3018.
222. Lebedeva, M. A., and Shadel, G. S. (2007) Cell Cycle, 6, 2048Ä2057.
223. Reinhard, H. C., and Yaffe, M. B. (2009) Curr. Opin. Cell Biol., 21, 245Ä255.
224. Eaton, J. S., Lin, Z. P., Sartorelli, A. C., et al. (2007) J. Clin. Invest., 117, 2723Ä2734.
225. Bochman, M., Sabouri, N., and Zakian, V. A. (2010) DNA Repair (Amst. ), 9,
237Ä249.
226. Makovets, S., and Blackburn, E. H. (2009) Nat. Cell Biol., 11, 1383Ä1386.
227. Meeusen, S., and Nunnari, J. (2003) J. Cell Biol., 163, 503Ä510.
228. Chen, X., Guan, M., and Clark-Walker, G. (1993) Nucleic Acids Res., 21,
3473Ä3477.
35
229. Mbantenkhu, M., Wang, X., Nardozzi, J., et al. (2011) J. Biol. Chem., 286, 42360Ä
42370.
230. Pan, X., Ye, P., Yuan, D. S., et al. (2006) Cell, 124, 1069Ä1081.
231. Šμ²Éμ¢ Ö, ., Š ·¢¨£ , ’. „., ‹Õ¡¨³μ¢ , Š. ., ¨ ¤·. (1998) ƒ¥´¥É¨± , 34,
610Ä624.
232. Loewen, C., Young, B., Tavassoli, S., and Levine, T. (2007) J. Cell. Biol., 179,
467Ä483.
233. Keaton, M. A., and Lew, D. J. (2006) Curr. Opin. Microbiol., 9, 540Ä546.
234. Babour, A., Bicknell, A. A., Tourtellotte, J., and Niwa, M. (2010) Cell, 142,
256Ä269.
235. Wittenberg, C., Richardson, S. L., and Reed, S. I. (1987) J. Cell Biol., 105,
1527Ä1538.
236. Verges, E., Colomina, N., Gari, E., et al. (2007) Mol. Cell, 26, 649Ä662.
237. Du, Y., Ferro-Novick, S., and Novick, P. (2004) J. Cell Sci., 117, 2871Ä2878.
238. Drubin, D. G., Jones, H. D., and Wertman, K. F. (1993) Mol. Biol. Cell, 4,
1277Ä1294.
239. Prinz, W. A., Grzyb, M., Veenhuis, J. A., et al. (2000) J. Cell Biol., 150, 461Ä474.
240. Park, H., Bi, E., Pringle, J. R., et al. (1997) Proc. Natl. Acad. Sci. USA, 94,
4463Ä4468.
241. Han, B. K., Bogomolnaya, L. M., Totte, J. M., et al. (2005) Genes Dev., 19,
2606Ä2616.
μ²ÊÎ¥´μ 15 μ±ÉÖ¡·Ö 2015 £.
¥¤ ±Éμ· …. ‚. ƒ·¨£μ·Ó¥¢ 줶¨¸ ´μ ¢ ¶¥Î ÉÓ 23.12.2015.
”μ·³ É 60 × 90/16. ʳ £ μ˸¥É´ Ö. ¥Î ÉÓ μ˸¥É´ Ö.
“¸². ¶¥Î. ². 2,43. “Î.-¨§¤. ². 2,93. ’¨· ¦ 205 Ô±§. ‡ ± § º 58719.
ˆ§¤ É¥²Ó¸±¨° μɤ¥² ¡Ñ¥¤¨´¥´´μ£μ ¨´¸É¨ÉÊÉ Ö¤¥·´ÒÌ ¨¸¸²¥¤μ¢ ´¨°
141980, £. „Ê¡´ , Œμ¸±μ¢¸± Ö μ¡²., ʲ. †μ²¨μ-ŠÕ·¨, 6.
E-mail: publish@jinr.ru
www.jinr.ru/publish/