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

Tardat, M.; Murr, R.; Herceg, Z.; Sardet, C.; Julien, E.

J Cell Biol

2007-12-31 / vol 179 / pages 1413-26


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.

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Cell Line, Tumor; Humans; Methylation; Histones/genetics/metabolism; Lysine/*metabolism; RNA, Small Interfering; Cell Cycle Proteins/genetics; DNA Damage/genetics; DNA Repair/genetics; DNA Replication/*genetics; DNA-Binding Proteins/genetics; Down-Regulation/genetics; Genomic Instability/*genetics; Histone-Lysine N-Methyltransferase/*genetics; Protein Processing, Post-Translational/*physiology; Protein-Serine-Threonine Kinases/genetics; S Phase/*genetics; Tumor Suppressor Proteins/genetics

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