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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的γ2AX去磷酸化：DNA修复和细胞周期控制中的一个重要稳态调节事件。

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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双链断裂是一种特别有毒的DNA损伤形式，哺乳动物细胞已经进化了复杂的反应，以修复这种类型的DNA病变。 DNA损伤反应（DDR）中的键早期事件是DNA断裂位点的丝氨酸139的组蛋白变体H2AX的ATM磷酸化。磷酸化的S139 H2AX或γ2ax形成用于结合MDC1的对接部位，从而持续招募其他DNA修复因子，介导DNA双链断裂的修复。此外，将MDC1募集到断裂点激活细胞周期检查点，保护细胞免受受损DNA模板的复制。虽然导致DNA双链断裂修复的分子事件已经熟悉，但在修复完成后的停用或稳态机制仍然很大程度上是未开发的。最近我们的实验室和Medema实验室的出版物在这个问题上阐述了新的光明。这两个出版物表明，野生型P53诱导的磷酸酶1（WIP1）直接去磷酸盐γ2AX。 WIP1迁移到辐射诱导的焦点（IRIF）的位置，但是在相对于MDC1的延迟速率下，介导γ2ax去磷酸化，可能是在DNA修复完成后。这可以防止招募其他修复因子，如MDC1和53bp1到DNA损伤部位并促进IRIF的溶解。此外，WIP1的过表达对DNA双链断裂修复具有抑制作用。总之，这些报告进一步暗示了WIP1作为DDR的关键稳态监管机构。

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