A PP4-phosphatase complex dephosphorylates gamma-H2AX generated during DNA replication.
A PP4-phosphatase complex dephosphorylates gamma-H2AX generated during DNA replication.
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DOI：
10.1016/j.molcel.2008.05.016
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发表时间：
2008-07-11
期刊：
影响因子：
16
通讯作者：
Lieberman, Judy
中科院分区：
文献类型：
--
作者：
Chowdhury, Dipanjan;Xu, Xingzhi;Zhong, Xueyan;Ahmed, Fariyal;Zhong, Jianing;Liao, Ji;Dykxhoorn, Derek M.;Weinstock, David M.;Pfeifer, Gerd P.;Lieberman, Judy
组蛋白H2 A变体H2 AX响应于DNA双链断裂而迅速磷酸化以产生γ-H2 AX。γ-H2 AX在断裂位点稳定细胞周期检查点蛋白和DNA修复因子。我们以前发现，蛋白磷酸酶PP 2A是解决γ-H2 AX灶和完成外源性DNA损伤后的DNA修复所必需的。在这里，我们描述了哺乳动物细胞中的三蛋白PP 4磷酸酶复合物，包含PP 4C，PP 4 R2和PP 4 R3 β，其特异性地使DNA复制期间产生的ATR介导的γ-H2 AX去磷酸化。PP 4在体外有效地使单核小体内的γ-H2 AX去磷酸化。PP 4对γ-H2 AX的作用不依赖于ATR和检查点激酶活性。当PP 4复合物被沉默时，DNA复制介导的断裂的修复是低效的，并且细胞对DNA复制抑制剂过敏，但对拟放射性药物不过敏。因此，DNA损伤修复需要在DNA损伤灶处消除γ-H2 AX，但完成这一任务涉及具有潜在重叠作用的不同磷酸酶。
The histone H2A variant H2AX is rapidly phosphorylated in response to DNA double-stranded breaks to produce γ-H2AX. γ-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 γ-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 PP4R3β, that specifically dephosphorylates ATR-mediated γ-H2AX generated during DNA replication. PP4 efficiently dephosphorylates γ-H2AX within mononucleosomes in vitro. The effect of PP4 on γ-H2AX is independent of ATR and checkpoint kinase activity. 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 γ-H2AX elimination at DNA damage foci is required for DNA damage repair, but accomplishing this task involves distinct phosphatases with potentially overlapping roles.
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