Cohesin acetylation speeds the replication fork.
Cohesin acetylation speeds the replication fork.
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作者：
粘连蛋白不仅连接姐妹染色单体，还抑制转录机制与染色质的相互作用和沿染色质的运动,,,,,。相反，复制叉必须穿过这种与粘连蛋白相关的障碍物，才能在 S 期复制整个基因组。这是如何发生的尚不清楚。通过单分子分析，我们证明复制因子 C (RFC)-CTF18 钳加载器 (RFFCCTF18) 控制人类细胞中复制叉的速度、间距和重新启动活动，并且是粘连蛋白 SMC3 亚基和姐妹染色单体凝聚的稳健乙酰化所必需的。出乎意料的是，我们发现粘连蛋白乙酰化本身是叉持续性的核心决定因素，因为在缺乏Eco1相关乙酰转移酶ESCO1或ESCO2（参考文献）的细胞（包括来自罗伯茨综合征患者的细胞，其中ESCO2发生双等位基因突变）和表达无法乙酰化的SMC3形式的细胞中发现了缓慢移动的复制叉。这种缺陷是粘连蛋白与两个调节辅助因子 WAPL 和 PDS5A 超稳定相互作用的结果（参考文献 , ）；去除任何一个辅助因子都可以在没有 ESCO1、ESCO2 或 RFCCTF18 的情况下使分叉快速进展。我们的结果显示了一种钳加载器依赖性叉进展的新机制，该机制是由粘连蛋白环的翻译后修饰和结构重塑介导的。这种调节机制的丧失会导致 DNA 损伤的自发累积，并可能导致罗伯茨综合征粘连病的异常。
Cohesin not only links sister chromatids but also inhibits the transcriptional machinery’s interaction with and movement along chromatin,,,,,. In contrast, replication forks must traverse such cohesin-associated obstructions to duplicate the entire genome in S phase. How this occurs is unknown. Through single-molecule analysis, we demonstrate that the replication factor C (RFC)–CTF18 clamp loader (RFCCTF18),controls the velocity, spacing and restart activity of replication forks in human cells and is required for robust acetylation of cohesin’s SMC3 subunit and sister chromatid cohesion. Unexpectedly, we discovered that cohesin acetylation itself is a central determinant of fork processivity, as slow-moving replication forks were found in cells lacking the Eco1-related acetyltransferases ESCO1 or ESCO2 (refs ) (including those derived from Roberts’ syndrome patients, in whomESCO2is biallelically mutated) and in cells expressing a form of SMC3 that cannot be acetylated. This defect was a consequence of cohesin’s hyperstable interaction with two regulatory cofactors, WAPL and PDS5A (refs , ); removal of either cofactor allowed forks to progress rapidly without ESCO1, ESCO2, or RFCCTF18. Our results show a novel mechanism for clamp-loader-dependent fork progression, mediated by the post-translational modification and structural remodelling of the cohesin ring. Loss of this regulatory mechanism leads to the spontaneous accrual of DNA damage and may contribute to the abnormalities of the Roberts’ syndrome cohesinopathy.
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影响因子：
64.8
作者：
Lengronne, A;Katou, Y;Mori, S;Yokobayashi, S;Kelly, GP;Itoh, T;Watanabe, Y;Shirahige, K;Uhlmann, F
通讯作者：
Uhlmann, F
DOI：
10.1073/pnas.1434308100
发表时间：
2003-09-02
影响因子：
11.1
作者：
Bermudez, VP;Maniwa, Y;Hurwitz, J
通讯作者：
Hurwitz, J
DOI：
10.1073/pnas.0701140104
发表时间：
2007-03-13
影响因子：
11.1
作者：
Burkard, Mark E.;Randall, Catherine L.;Jallepalli, Prasad V.
通讯作者：
Jallepalli, Prasad V.
影响因子：
16
作者：
Ishihara, Ko;Oshimura, Mitsuo;Nakao, Mitsuyoshi
通讯作者：
Nakao, Mitsuyoshi
影响因子：
9.2
作者：
Gandhi, Rita;Gillespie, Peter J.;Hirano, Tatsuya
通讯作者：
Hirano, Tatsuya