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

Tardat, Mathieu
Herceg, Zdenko
Sardet, Claude
Julien, Eric
Published in The Journal of Cell Biology. 2007, vol. 179, no. 7, p. 1413-26
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 ProteinsCell Cycle Proteins/geneticsCell Line, TumorDNA Damage/geneticsDNA Repair/geneticsDNA Replication/geneticsDNA-Binding Proteins/geneticsDown-Regulation/geneticsGenomic Instability/geneticsHistone-Lysine N-Methyltransferase/geneticsHistones/genetics/metabolismHumansLysine/metabolismMethylationProtein Processing, Post-Translational/physiologyProtein-Serine-Threonine Kinases/geneticsRNA, Small InterferingS Phase/geneticsTumor Suppressor Proteins/genetics
PMID: 18158331
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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. 1413-26. doi: 10.1083/jcb.200706179

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Deposited on : 2014-12-17

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