Qin Bo, Yu Jia, Zhao Fei, Huang Jinzhou, Zhou Qin, Lou Zhenkun
Department of Oncology, Mayo Clinic, Rochester, MN 55905 USA.
Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905 USA.
Genome Instab Dis. 2022;3(4):217-226. doi: 10.1007/s42764-022-00076-z. Epub 2022 Aug 10.
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.
泛素样修饰连接酶-UFL1在双链断裂（DSB）发生后的正反馈回路中，通过在H4的K31位点进行单泛素样修饰来促进ATM激活，而泛素样修饰特异性蛋白酶2（UfSP2）则抑制ATM激活，但UfSP2募集到DSB以微调DNA损伤反应的机制仍不清楚。在此，我们报告，与辐射损伤后UFL1病灶形成相比，UfSP2病灶形成延迟。从机制上讲，UfSP2在没有DSB的情况下与MRN复合物结合。ATM诱导的UfSP2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去除，从而使UfSP2被募集到DSB，使H4去泛素样修饰并抑制ATM激活。总之，我们确定了一种UfSP2对ATM激活进行精细负调控的机制，并重新连接了ATM激活途径。
