TET3-mediated DNA oxidation promotes ATR-dependent DNA damage response.
An efficient, accurate, and timely DNA damage response (DDR) is crucial for the maintenance of genome integrity. Here, we report that ten-eleven translocation dioxygenase (TET) 3-mediated conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in response to ATR-dependent DDR regulates DNA repair. ATR-dependent DDR leads to dynamic changes in 5hmC levels and TET3 enzymatic activity. We show that TET3 is an ATR kinase target that oxidizes DNA during ATR-dependent DNA damage repair. Modulation of TET3 expression and activity affects DNA damage signaling and DNA repair and consequently cell death. Our results provide novel insight into ATR-mediated DDR, in which TET3-mediated DNA demethylation is crucial for efficient DNA repair and maintenance of genome stability.
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, China.
Dewei
D
Jiang
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, China.|Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China.
Shu
S
Wei
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, China.
Fei
F
Chen
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, China.
Ying
Y
Zhang
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, China lijiali@mail.kiz.ac.cn.|Kunming Primate Research Center of the Chinese Academy of Sciences, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming, China.
Jiali
0000-0002-0039-3671
J
Li
D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D016678:Genome; D051379:Mice; D010084:Oxidation-Reduction; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D004247:DNA; D049308:Dioxygenases; C551915:Tet3 protein, mouse; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins
5hmC; ATR; DNA damage response; DNA demethylation; TET3