Details

Autor(en) / Beteiligte

• Zhang, Canfeng
• Chen, Liping
• Peng, Di
• Jiang, Ao
• He, Yunru
• Zeng, Yanru
• Xie, Chen
• Zhou, Haoxian
• Luo, Xiaotong
• Liu, Haiying
• Chen, Liang
• Ren, Jian
• Wang, Wengong
• Zhao, Yong

Titel

METTL3 and N6-Methyladenosine Promote Homologous Recombination-Mediated Repair of DSBs by Modulating DNA-RNA Hybrid Accumulation

Ist Teil von

• Molecular cell, 2020-08, Vol.79 (3), p.425-442.e7

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2020

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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. [Display omitted] •METTL3 is phosphorylated at S43 by ATM and localized to DSB sites•m6A-modifed RNA by METTL3 is enriched at DSBs that recruit YTHDC1 for protection•METTL3-m6A-YTHDC1 axis increases accumulation of DNA-RNA hybrids at DSBs•METTL3 deficiency sensitizes cancers to chemo and/or radiotherapy Zhang et al. find that METTL3 is phosphorylated by ATM at S43 and recruited to DSBs, where it catalyzes m6A modification on DNA damage-associated RNA, which is recognized and protected by YTHDC1. Thus, the METTL3-m6A-YTHDC1 axis increases accumulation of DNA-RNA hybrids at DSBs that recruit RAD51 and BRCA1 for HR-mediated DSBR.