en
Scientific article
English

PR-Set7-dependent lysine methylation ensures genome replication and stability through S phase

Published inThe Journal of cell biology, vol. 179, no. 7, p. 1413-1426
Publication date2007
Abstract

PR-Set7/SET8 is a histone H4-lysine 20 methyltransferase required for normal cell proliferation. However, the exact functions of this enzyme remain to be determined. In this study, we show that human PR-Set7 functions during S phase to regulate cellular proliferation. PR-Set7 associates with replication foci and maintains the bulk of H4-K20 mono- and trimethylation. Consistent with a function in chromosome dynamics during S phase, inhibition of PR-Set7 methyltransferase activity by small hairpin RNA causes a replicative stress characterized by alterations in replication fork velocity and origin firing. This stress is accompanied by massive induction of DNA strand breaks followed by a robust DNA damage response. The DNA damage response includes the activation of ataxia telangiectasia mutated and ataxia telangiectasia related kinase-mediated pathways, which, in turn, leads to p53-mediated growth arrest to avoid aberrant chromosome behavior after improper DNA replication. Collectively, these data indicate that PR-Set7-dependent lysine methylation during S phase is an essential posttranslational mechanism that ensures genome replication and stability.

Keywords
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins/genetics
  • Cell Line, Tumor
  • DNA Damage/genetics
  • DNA Repair/genetics
  • DNA Replication/genetics
  • DNA-Binding Proteins/genetics
  • Down-Regulation/genetics
  • Genomic Instability/genetics
  • Histone-Lysine N-Methyltransferase/genetics
  • Histones/genetics/metabolism
  • Humans
  • Lysine/metabolism
  • Methylation
  • Protein Processing, Post-Translational/physiology
  • Protein-Serine-Threonine Kinases/genetics
  • RNA, Small Interfering
  • S Phase/genetics
  • Tumor Suppressor Proteins/genetics
Affiliation Not a UNIGE publication
Citation (ISO format)
TARDAT, Mathieu et al. PR-Set7-dependent lysine methylation ensures genome replication and stability through S phase. In: The Journal of cell biology, 2007, vol. 179, n° 7, p. 1413–1426. doi: 10.1083/jcb.200706179
Main files (1)
Article (Published version)
accessLevelRestricted
Identifiers
ISSN of the journal0021-9525
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