Cohesin acetylation speeds the replication fork

Nature. 2009 Nov 12;462(7270):231-4. doi: 10.1038/nature08550.

Abstract

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 (RFC(CTF18)) 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 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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Acetylation
  • Acetyltransferases / deficiency
  • Acetyltransferases / genetics
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Cellular Senescence
  • Chromatids / metabolism
  • Chromosomal Proteins, Non-Histone / chemistry
  • Chromosomal Proteins, Non-Histone / deficiency
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA Damage
  • DNA Replication / drug effects
  • DNA Replication / physiology*
  • Humans
  • Mutagens / toxicity
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Subunits / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Replication Protein C / metabolism

Substances

  • CHTF18 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • MGC5528 protein, human
  • Mutagens
  • Nuclear Proteins
  • PDS5A protein, human
  • Protein Subunits
  • Proto-Oncogene Proteins
  • WAPAL protein, human
  • cohesins
  • Acetyltransferases
  • ESCO1 protein, human
  • ESCO2 protein, human
  • ATPases Associated with Diverse Cellular Activities
  • Replication Protein C