Dephosphorylation of γ-H2AX by WIP1: an important homeostatic regulatory event in DNA repair and cell cycle control.
Dephosphorylation of γ-H2AX by WIP1: an important homeostatic regulatory event in DNA repair and cell cycle control.
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DOI：
10.4161/cc.9.11.11810
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发表时间：
2010-06-01
期刊：
影响因子：
--
通讯作者：
Donehower LA
中科院分区：
文献类型：
--
作者：
Moon SH;Nguyen TA;Darlington Y;Lu X;Donehower LA
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出一套复杂的反应来修复这种类型的DNA损伤。DNA损伤反应(DDR)的一个关键早期事件是组蛋白变异体H_2AX在DNA断裂部位的丝氨酸139处的ATM磷酸化。磷酸化的S139 H_2AX，或DNAH_2AX，形成与γ结合的对接位置，导致其他介导DNA双链断裂修复的DNA修复因子的持续募集。此外，MDC1在断裂位点上的招募激活了细胞周期检查点，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被很好地描述，但修复完成后的失活或稳态机制在很大程度上仍未被探索。我们的实验室和Medema实验室最近发表的出版物为这一问题提供了新的线索。这两篇文献都表明，野生型P53诱导的磷酸酶1(WIP1)直接使γH2AX去磷酸化。Wip1迁移到辐射诱导灶(IRIF)的位置，尽管相对于mdc1有延迟的速度，并介导γH_2AX去磷酸化，推测是在DNA修复完成之后。这阻止了MDC1和53BP1等其他修复因子在DNA损伤部位的募集，并促进了IRIF的溶解。此外，Wip1的过表达对DNA双链断裂修复有抑制作用。综上所述，这些报告进一步暗示Wip1是DDR的一个关键的动态平衡调节因子。
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 γH2AX, 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 γH2AX. WIP1 migrates to the sites of irradiation-induced foci (IRIF), though at a delayed rate relative to MDC1 and mediates γH2AX 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.
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影响因子：
16
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
通讯作者：
Lieberman, Judy
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
DOI：
10.1073/pnas.0603779103
发表时间：
2006-06-27
影响因子：
11.1
作者：
Marti, Thomas M.;Hefner, Eli;Cleaver, James E.
通讯作者：
Cleaver, James E.
DOI：
10.1073/pnas.94.12.6048
发表时间：
1997-06-10
影响因子：
11.1
作者：
Fiscella, M;Zhang, HL;Appella, E
通讯作者：
Appella, E
影响因子：
5.3
作者：
Douglas, Pauline;Zhong, Jianing;Lees-Miller, Susan P.
通讯作者：
Lees-Miller, Susan P.