MRE11 UFMylation promotes ATM activation
MRE11 UFMylation promotes ATM activation
复制标题
MRE11 UFMylation 促进 ATM 激活
DOI：
10.1093/nar/gkz110
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发表时间：
2019-05-07
影响因子：
14.9
通讯作者：
Xu, Xingzhi
中科院分区：
文献类型：
--
作者：
Wang, Zhifeng;Gong, Yamin;Xu, Xingzhi
适当的DNA损伤反应（DDR）对于维持基因组完整性和预防肿瘤发生至关重要。DNA双链断裂（DSB）是最具毒性的DNA损伤，其修复由ATM激酶协调。ATM通过MRE 11-RAD 50-NBS 1（MRN）复合物沿着其在S1981处的自磷酸化和在K3106处的乙酰化而被激活。激活的ATM迅速磷酸化大量的底物在当地的染色质，提供了一个支架组装的高阶复合物，可以修复受损的DNA。虽然可逆的泛素化在DSB反应中具有重要作用，但新鉴定的泛素样蛋白泛素折叠修饰剂1的修饰和UFM化在DDR中的功能在很大程度上是未知的。在这里，我们发现MRE 11在K282上被UFM化，并且这种UFM化是在未扰动条件下MRN复合物形成和DSB诱导的最佳ATM活化、同源重组介导的修复和基因组完整性所必需的。在子宫内膜样癌中鉴定的致病突变MRE 11（G285 C）表现出与UFMylation缺陷突变MRE 11（K282 R）相似的细胞表型。总之，MRE 11 UFM化促进ATM活化、DSB修复和基因组稳定性，并可能作为治疗靶点。
A proper DNA damage response (DDR) is essential to maintain genome integrity and prevent tumorigenesis. DNA double-strand breaks (DSBs) are the most toxic DNA lesion and their repair is orchestrated by the ATM kinase. ATM is activated via the MRE11-RAD50-NBS1 (MRN) complex along with its autophosphorylation at S1981 and acetylation at K3106. Activated ATM rapidly phosphorylates a vast number of substrates in local chromatin, providing a scaffold for the assembly of higher-order complexes that can repair damaged DNA. While reversible ubiquitination has an important role in the DSB response, modification of the newly identified ubiquitin-like protein ubiquitin-fold modifier 1 and the function of UFMylation in the DDR is largely unknown. Here, we found that MRE11 is UFMylated on K282 and this UFMylation is required for the MRN complex formation under unperturbed conditions and DSB-induced optimal ATM activation, homologous recombination-mediated repair and genome integrity. A pathogenic mutation MRE11(G285C) identified in uterine endometrioid carcinoma exhibited a similar cellular phenotype as the UFMylation-defective mutant MRE11(K282R). Taken together, MRE11 UFMylation promotes ATM activation, DSB repair and genome stability, and potentially serves as a therapeutic target.