| Literature DB >> 18614045 |
Dipanjan Chowdhury1, Xingzhi Xu, Xueyan Zhong, Fariyal Ahmed, Jianing Zhong, Ji Liao, Derek M Dykxhoorn, David M Weinstock, Gerd P Pfeifer, Judy Lieberman.
Abstract
The histone H2A variant H2AX is rapidly phosphorylated in response to DNA double-stranded breaks to produce gamma-H2AX. gamma-H2AX stabilizes cell-cycle checkpoint proteins and DNA repair factors at the break site. We previously found that the protein phosphatase PP2A is required to resolve gamma-H2AX foci and complete DNA repair after exogenous DNA damage. Here we describe a three-protein PP4 phosphatase complex in mammalian cells, containing PP4C, PP4R2, and PP4R3beta, that specifically dephosphorylates ATR-mediated gamma-H2AX generated during DNA replication. PP4 efficiently dephosphorylates gamma-H2AX within mononucleosomes in vitro and does not directly alter ATR or checkpoint kinase activity, suggesting that PP4 acts directly on gamma-H2AX in cells. When the PP4 complex is silenced, repair of DNA replication-mediated breaks is inefficient, and cells are hypersensitive to DNA replication inhibitors, but not radiomimetic drugs. Therefore, gamma-H2AX elimination at DNA damage foci is required for DNA damage repair, but accomplishing this task involves distinct phosphatases with potentially overlapping roles.Entities:
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Year: 2008 PMID： 18614045 PMCID： PMC3242369 DOI： 10.1016/j.molcel.2008.05.016
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970