Dynamic recruitment of UFM1-specific peptidase 2 to the DNA double-strand breaks regulated by WIP1.
Dynamic recruitment of UFM1-specific peptidase 2 to the DNA double-strand breaks regulated by WIP1.
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DOI：
10.1007/s42764-022-00076-z
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Lou, Zhenkun
中科院分区：
文献类型：
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作者：
Qin, Bo;Yu, Jia;Zhao, Fei;Huang, Jinzhou;Zhou, Qin;Lou, Zhenkun
Ufm化连接酶-UFl1通过在双链断裂(DSB)发生后，在正反馈环中单甲基化K31位的H4来促进ATM的激活，而UFM1特异性多肽酶2(UfSP2)抑制ATM的激活，但UfSP2募集到DSB微调DNA损伤反应的机制尚不清楚。在这里，我们报告了在辐射损伤后，UfSP2焦点的形成比UFl1焦点的形成延迟。从机械上讲，在没有DSB的情况下，UfSP2与MRN复合体结合。辐射诱导ATM对UfSP2的磷酸化导致UfSP2从MRN复合体中解离。这种磷酸化可以被磷酸酶Wip1去除，从而UfSP2被招募到DSB，去甲基化H4并抑制ATM激活。综上所述，我们确定了UfSP2对ATM激活的一种微妙的负调控机制，并重新连接了ATM激活途径。
The ufmylation ligase-UFL1 promotes ATM activation by monoufmylating H4 at K31 in a positive-feedback loop after double-strand breaks (DSB) occur, whereas UFM1 Specific Peptidase 2 (UfSP2) suppresses ATM activation, but the mechanism of recruitment of UfSP2 to the DSB finetuning DNA damage response is still not clear. Here, we report that UfSP2 foci formation is delayed compared to UFL1 foci formation following the radiation insult. Mechanistically, UfSP2 binds to the MRN complex in absence of DSB. Irradiation-induced phosphorylation of UfSP2 by ATM leads to the dissociation of UfSP2 from the MRN complex. This phosphorylation can be removed by the phosphatase WIP1, thereby UfSP2 is recruited to the DSBs, deufmylating H4 and suppressing ATM activation. In summary, we identify a mechanism of delicately negative modulation of ATM activation by UfSP2 and rewires ATM activation pathways.