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首页> 外文期刊>Cell cycle >Dephosphorylation of gammaH2AX by WIP1: An important homeostatic regulatory event in DNA repair and cell cycle control.
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Dephosphorylation of gammaH2AX by WIP1: An important homeostatic regulatory event in DNA repair and cell cycle control.

机译：WIP1对gammaH2AX的去磷酸化：DNA修复和细胞周期控制中的重要稳态调节事件。

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DNA double strand breaks are a particularly toxic form of DNA damage and the mammalian cell has evolved an intricate set of responses to repair this type of DNA lesion. A key early event in the DNA damage response (DDR) is ATM phosphorylation of the histone variant H2AX at serine 139 at the site of the DNA break. Phosphorylated S139 H2AX, or gammaH2AX, forms a docking site for binding of MDC1, leading to sustained recruitment of other DNA repair factors that mediate the repair of the DNA double strand break. Moreover, recruitment of MDC1 to the break site activates cell cycle checkpoints, protecting the cell from replication of damaged DNA templates. While the molecular events leading to DNA double strand break repair have been well described, the deactivating or homeostatic mechanisms following completion of repair remain largely unexplored. Recent publications by our laboratories and the Medema laboratory shed new light on this issue. Both publications showed that the Wild-type p53-Induced Phosphatase 1 (WIP1) directly dephosphorylates gammaH2AX. WIP1 migrates to the sites of irradiation-induced foci (IRIF), though at a delayed rate relative to MDC1 and mediates gammaH2AX dephosphorylation, presumably after DNA repair is complete. This prevents recruitment of other repair factors such as MDC1 and 53BP1 to the DNA damage sites and promotes the dissolution of IRIF. In addition, overexpression of WIP1 has a suppressive effect on DNA double strand break repair. Taken together, these reports further implicate WIP1 as a critical homeostatic regulator of the DDR.
机译：DNA双链断裂是DNA损伤的一种特别有毒的形式，哺乳动物细胞已经进化出一系列复杂的反应来修复这种类型的DNA损伤。 DNA损伤反应（DDR）中的关键早期事件是DNA断裂位点的丝氨酸139处的组蛋白变体H2AX的ATM磷酸化。磷酸化的S139 H2AX或gammaH2AX形成MDC1结合的停靠位点，导致其他DNA修复因子的持续募集，这些因子介导DNA双链断裂的修复。此外，将MDC1募集到断裂位点会激活细胞周期检查点，从而保护细胞免受复制的受损DNA模板的侵害。尽管已经详细描述了导致DNA双链断裂修复的分子事件，但是修复完成后的失活或体内平衡机制仍未开发。我们实验室和Medema实验室的最新出版物为这个问题提供了新的思路。两种出版物均表明，野生型p53诱导的磷酸酶1（WIP1）直接使gammaH2AX脱磷酸化。 WIP1迁移到辐射诱导病灶（IRIF）的位置，尽管相对于MDC1延迟了，并介导了gammaH2AX的去磷酸化，大概是在DNA修复完成之后。这样可以防止其他修复因子（例如MDC1和53BP1）募集到DNA损伤位点，并促进IRIF的溶解。另外，WIP1的过表达对DNA双链断裂修复具有抑制作用。总而言之，这些报告进一步暗示WIP1是DDR的关键稳态稳压器。

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