Cohesin acetylation speeds the replication fork Journal Article
| Authors: | Terret, M. E.; Sherwood, R.; Rahman, S.; Qin, J.; Jallepalli, P. V. |
| Article Title: | Cohesin acetylation speeds the replication fork |
| Abstract: | Cohesin not only links sister chromatids but also inhibits the transcriptional machinerys 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 (RFC CTF18) controls the velocity, spacing and restart activity of replication forks in human cells and is required for robust acetylation of cohesins 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 mutated) and in cells expressing a form of SMC3 that cannot be acetylated. This defect was a consequence of cohesins 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 RFC CTF18. 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. © 2009 Macmillan Publishers Limited. All rights reserved. |
| Keywords: | controlled study; unclassified drug; human cell; proto-oncogene proteins; dna replication; cohesin; chromosome; cell cycle proteins; chromosomal proteins, non-histone; dna damage; gene expression; embryo; cell line; protein; protein stability; protein interaction; chromatid; nuclear proteins; dna; carrier proteins; molecular analysis; rna translation; dna structure; hominid; replication factor c; protein subunits; replication protein c; protein structure; cell adhesion; cell aging; acyltransferase; acetyltransferases; heritability; protein modification; acetylation; velocity; esco 1 protein; esco protein 2; pds5a protein; smc 3 protein; wapl protein; abnormality; cohesion; replication fork; roberts syndrome; chromatids; mutagens |
| Journal Title: | Nature |
| Volume: | 462 |
| Issue: | 7270 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2009-11-12 |
| Start Page: | 231 |
| End Page: | 234 |
| Language: | English |
| DOI: | 10.1038/nature08550 |
| PUBMED: | 19907496 |
| PROVIDER: | scopus |
| PMCID: | PMC2777716 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 18" - "Export Date: 30 November 2010" - "CODEN: NATUA" - "Source: Scopus" |
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5Rahman
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