雷达51
同源重组
生物
基因组不稳定性
DNA损伤
核糖核酸
DNA
细胞生物学
非同源性末端接合
分子生物学
DNA修复
癌症研究
遗传学
基因
作者
Canfeng Zhang,Liping Chen,Di Peng,Ao Jiang,Yunru He,Yanru Zeng,Chen Xie,Huan Zhou,Xiaotong Luo,Haiying Liu,Chen Liang,Jian Ren,Wengong Wang,Yong Zhao
出处
期刊:Molecular Cell
[Elsevier]
日期:2020-08-01
卷期号:79 (3): 425-442.e7
被引量:159
标识
DOI:10.1016/j.molcel.2020.06.017
摘要
Double-strand breaks (DSBs) are the most deleterious DNA lesions, which, if left unrepaired, may lead to genome instability or cell death. Here, we report that, in response to DSBs, the RNA methyltransferase METTL3 is activated by ATM-mediated phosphorylation at S43. Phosphorylated METTL3 is then localized to DNA damage sites, where it methylates the N6 position of adenosine (m6A) in DNA damage-associated RNAs, which recruits the m6A reader protein YTHDC1 for protection. In this way, the METTL3-m6A-YTHDC1 axis modulates accumulation of DNA-RNA hybrids at DSBs sites, which then recruit RAD51 and BRCA1 for homologous recombination (HR)-mediated repair. METTL3-deficient cells display defective HR, accumulation of unrepaired DSBs, and genome instability. Accordingly, depletion of METTL3 significantly enhances the sensitivity of cancer cells and murine xenografts to DNA damage-based therapy. These findings uncover the function of METTL3 and YTHDC1 in HR-mediated DSB repair, which may have implications for cancer therapy.
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