在 WIP1 的调控下,UFM1 特异性肽酶 2 被动态招募到 DNA 双链断裂处。

Genome instability & disease Pub Date : 2022-01-01 Epub Date: 2022-08-10 DOI:10.1007/s42764-022-00076-z
Bo Qin, Jia Yu, Fei Zhao, Jinzhou Huang, Qin Zhou, Zhenkun Lou
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引用次数: 0

摘要

双链断裂(DSB)发生后,ufmylation连接酶-UFL1通过在K31处对H4进行单ufmylation促进ATM活化,而UFM1特异性肽酶2(UfSP2)则抑制ATM活化,但UfSP2招募到DSB微调DNA损伤反应的机制仍不清楚。在这里,我们报告了与 UFL1 的形成相比,UfSP2 的形成在辐射损伤后会延迟。从机制上讲,UfSP2 在没有 DSB 的情况下与 MRN 复合物结合。辐照诱导的 ATM 对 UfSP2 的磷酸化导致 UfSP2 从 MRN 复合物中解离。这种磷酸化可被磷酸酶 WIP1 清除,从而使 UfSP2 被招募到 DSB,使 H4 去淀粉酰化并抑制 ATM 的活化。总之,我们发现了 UfSP2 对 ATM 激活的微妙负向调节机制,并重新构建了 ATM 激活途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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.

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.

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.

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