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Published online December 24, 2007
doi:10.1083/jcb.200706179
The Journal of Cell Biology, Vol. 179, No. 7, 1413-1426
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Tardat et al.
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Article

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

Mathieu Tardat1,2, Rabih Murr3, Zdenko Herceg3, Claude Sardet1,2, and Eric Julien1,2

1 University of Montpellier II, Institut de Génétique Moléculaire de Montpellier, 34293 Montpellier, Cedex 5, France
2 Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5535, Institut Fédératif de Recherche 122, 34293 Montpellier, France
3 International Agency for Research on Cancer, World Health Organization, 69372 Lyon, France

Correspondence to Claude Sardet: claude.sardet{at}igmm.cnrs.fr; or Eric Julien: eric.julien{at}igmm.cnrs.fr

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.

Abbreviations used in this paper: 7AAD, 7-amino-actinomycin D; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia related; CldU, chlorodeoxyuridine; HNF, human normal fibroblast; IdU, iododeoxyuridine; shRNA, small hairpin RNA.


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