Wang Yang, Yu Tianyu, Han Yi, He Yazhi, Song Yiran, Guo Leiming, An Liwei, Yang Chunying, Wang Feng
Department of Gastroenterology, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai, China.
Department of General Surgery, Pudong New Area Gongli Hospital Affiliated to Naval Military Medical University, Naval Military Medical University, Shanghai, China.
Front Cell Dev Biol. 2022 Mar 2;10:817831. doi: 10.3389/fcell.2022.817831. eCollection 2022.
The spindle assembly checkpoint (SAC) is a critical monitoring device in mitosis for the maintenance of genomic stability. Specifically, the SAC complex comprises several factors, including Mad1, Mad2, and Bub1. Ataxia-telangiectasia mutated (ATM) kinase, the crucial regulator in DNA damage response (DDR), also plays a critical role in mitosis by regulating Mad1 dimerization and SAC. Here, we further demonstrated that ATM negatively regulates the phosphorylation of Mad2, another critical component of the SAC, which is also involved in DDR. Mechanistically, we found that phosphorylation of Mad2 is aberrantly increased in ATM-deficient cells. Point-mutation analysis further revealed that Serine 195 mainly mediated Mad2 phosphorylation upon ATM ablation. Functionally, the phosphorylation of Mad2 causes decreased DNA damage repair capacity and is related to the resistance to cancer cell radiotherapy. Altogether, this study unveils the key regulatory role of Mad2 phosphorylation in checkpoint defects and DNA damage repair in ATM-deficient cells.
纺锤体组装检查点（SAC）是有丝分裂过程中维持基因组稳定性的关键监测机制。具体而言，SAC复合物包含多种因子，包括Mad1、Mad2和Bub1。共济失调毛细血管扩张症突变（ATM）激酶是DNA损伤反应（DDR）中的关键调节因子，它还通过调节Mad1二聚化和SAC在有丝分裂中发挥关键作用。在此，我们进一步证明ATM负向调节SAC的另一个关键成分Mad2的磷酸化，Mad2也参与DDR。从机制上讲，我们发现Mad2的磷酸化在ATM缺陷细胞中异常增加。点突变分析进一步揭示，丝氨酸195在ATM缺失时主要介导Mad2磷酸化。在功能上，Mad2的磷酸化导致DNA损伤修复能力下降，并与癌细胞放疗抗性有关。总之，本研究揭示了Mad2磷酸化在ATM缺陷细胞的检查点缺陷和DNA损伤修复中的关键调节作用。
