DNA damage-induced YTHDC1 O-GlcNAcylation promotes homologous recombination by enhancing m6A binding

IF 6.2 3区综合性期刊 Q1 Multidisciplinary

Fundamental Research Pub Date : 2025-03-01 DOI:10.1016/j.fmre.2023.04.017

Mengyao Li , Jie Li , Yibo Wang , Jianxin Zhao , Aiyun Yuan , Weidong Dong , Linlin Kong , Suwei Dong , Weijie Qin , Yun-Gui Yang , Xiaohui Wang , Chen Wu , Jing Li

{"title":"DNA damage-induced YTHDC1 O-GlcNAcylation promotes homologous recombination by enhancing m6A binding","authors":"Mengyao Li , Jie Li , Yibo Wang , Jianxin Zhao , Aiyun Yuan , Weidong Dong , Linlin Kong , Suwei Dong , Weijie Qin , Yun-Gui Yang , Xiaohui Wang , Chen Wu , Jing Li","doi":"10.1016/j.fmre.2023.04.017","DOIUrl":null,"url":null,"abstract":"<div><div>N6-methyladenosine (m<sup>6</sup>A) is the most prevalent internal RNA modification, and its regulators include writers, readers and erasers. m<sup>6</sup>A is under stringent control and takes part in many biological events, but it is not known whether there is an interplay between m<sup>6</sup>A and glycosylation. Here we investigated an m<sup>6</sup>A reader, YTHDC1, which has been shown to be recruited to the DNA-RNA hybrid at DNA damage sites and regulate homologous recombination (HR) during DNA damage repair. We found that YTHDC1 is subject to O-linked β-N-acetylglucosamine (O-GlcNAc) modification at Ser396 upon DNA damage, which is pivotal for YTHDC1 chromatin binding and ionization radiation induced focus (IRIF) formation. RNA immunoprecipitation (RIP) and molecular dynamics (MD) simulations indicate that O-GlcNAcylation is vital for YTHDC1 to bind with m<sup>6</sup>A RNA. Fluorescence recovery after photo bleaching (FRAP) analysis revealed that YTHDC1 O-GlcNAcylation is essential for DNA damage-induced YTHDC1-m<sup>6</sup>A condensate formation. We further demonstrate that YTHDC1 O-GlcNAcylation promotes HR-mediated DNA damage repair and cell survival, probably through recruitment of Rad51 to the damage sites. We propose that YTHDC1 O-GlcNAcylation is instrumental for HR.</div></div>","PeriodicalId":34602,"journal":{"name":"Fundamental Research","volume":"5 2","pages":"Pages 868-879"},"PeriodicalIF":6.2000,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Fundamental Research","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2667325823001711","RegionNum":3,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Multidisciplinary","Score":null,"Total":0}

引用次数: 0

Abstract

N6-methyladenosine (m⁶A) is the most prevalent internal RNA modification, and its regulators include writers, readers and erasers. m⁶A is under stringent control and takes part in many biological events, but it is not known whether there is an interplay between m⁶A and glycosylation. Here we investigated an m⁶A reader, YTHDC1, which has been shown to be recruited to the DNA-RNA hybrid at DNA damage sites and regulate homologous recombination (HR) during DNA damage repair. We found that YTHDC1 is subject to O-linked β-N-acetylglucosamine (O-GlcNAc) modification at Ser396 upon DNA damage, which is pivotal for YTHDC1 chromatin binding and ionization radiation induced focus (IRIF) formation. RNA immunoprecipitation (RIP) and molecular dynamics (MD) simulations indicate that O-GlcNAcylation is vital for YTHDC1 to bind with m⁶A RNA. Fluorescence recovery after photo bleaching (FRAP) analysis revealed that YTHDC1 O-GlcNAcylation is essential for DNA damage-induced YTHDC1-m⁶A condensate formation. We further demonstrate that YTHDC1 O-GlcNAcylation promotes HR-mediated DNA damage repair and cell survival, probably through recruitment of Rad51 to the damage sites. We propose that YTHDC1 O-GlcNAcylation is instrumental for HR.

Abstract Image