整合素环在细胞分裂过程中围绕着姐妹DNA分子对，使它们能够正确分开。这些环抑制转录细胞器的进程，但并不阻止复制细胞器在细胞周期的S-阶段复制基因组。现在，单分子分析表明，一个复制复合物（被称为复制因子C–CTF18 clamp loader）使整合素乙酰化，从而减低整合素与调控因子的关联，推动复制叉的进程。乙酰化的失去（如在罗伯茨综合征患者的细胞中所观察到的那样），会造成叉进程的缺陷及DNA损伤的积累。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature 462, 231-234 (12 November 2009) | doi:10.1038/nature08550
Cohesin acetylation speeds the replication fork
Marie-Emilie Terret1, Rebecca Sherwood1, Sadia Rahman1, Jun Qin2 & Prasad V. Jallepalli1
1 Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA
2 Center for Molecular Discovery, Verna and Marrs McLean, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
3 Correspondence to: Prasad V. Jallepalli1 Correspondence and requests for materials should be addressed to P.V.J.
Cohesin not only links sister chromatids but also inhibits the transcriptional machinery's interaction with and movement along chromatin1, 2, 3, 4, 5, 6. 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)1, 7 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 8–10) (including those derived from Roberts' syndrome patients, in whom ESCO2 is biallelically mutated11) 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 12, 13); 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.
