ATM-mediated KDM2A phosphorylation is required for the DNA damage repair

被引：56

作者：

Cao, L-L ^{[1
]}

Wei, F. ^{[1
]}

Du, Y. ^{[1
]}

Song, B. ^{[1
]}

Wang, D. ^{[1
]}

Shen, C. ^{[1
]}

Lu, X. ^{[1
]}

Cao, Z. ^{[1
]}

Yang, Q. ^{[1
]}

Gao, Y. ^{[2
]}

Wang, L. ^{[1
]}

Zhao, Y. ^{[1
]}

Wang, H. ^{[1
]}

Yang, Y. ^{[1
]}

Zhu, W-G ^{[1
,3
]}

机构：

[1] Peking Univ, Hlth Sci Ctr,Dept Biochem & Mol Biol,Sch Basic Me, Key Lab Carcinogenesis & Translat Res Minist Educ, State Key Lab Nat & Biomimet Drugs,Beijing Key La, Beijing 100871, Peoples R China

[2] Tsinghua Univ, Sch Biol Sci, Prot Chem Facil, Beijing 100084, Peoples R China

[3] Peking Univ Tsinghua Univ Joint Ctr Life Sci, Beijing, Peoples R China

来源：

ONCOGENE | 2016年 / 35卷 / 03期

基金：

中国国家自然科学基金;

关键词：

DOUBLE-STRAND BREAKS; MRE11-RAD50-NBS1; COMPLEX; HOMOLOGOUS RECOMBINATION; HISTONE DEMETHYLASE; CELLULAR-RESPONSE; MRE11; METHYLATION; PROTEIN; CHECKPOINT; PROMOTES;

D O I：

10.1038/onc.2015.81

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The ataxia-telangiectasia mutated (ATM) protein is a key signaling molecule that modulates the DNA damage response. However, the exact mechanism by which ATM regulates DNA damage repair has not yet been elucidated. Here, we report that ATM regulates the DNA damage response by phosphorylating lysine-specific demethylase 2A (KDM2A), a histone demethylase that acts at sites of H3K36 dimethylation. ATM interacts with KDM2A, and their interaction significantly increases in response to DNA double-stranded, but not single-stranded, breaks. ATM specifically phosphorylates KDM2A at threonine 632 (T632) following DNA damage, as demonstrated by a mutagenesis assay and mass spectrometric analysis. Although KDM2A phosphorylation does not alter its own demethylase activity, T632 phosphorylation of KDM2A largely abrogates its chromatin-binding capacity, and H3K36 dimethylation near DNA damage sites is significantly increased. Consequently, enriched H3K36 dimethylation serves as a platform to recruit the MRE11 complex to DNA damage sites by directly interacting with the BRCT2 domain of NBS1, which results in efficient DNA damage repair and enhanced cell survival. Collectively, our study reveals a novel mechanism for ATM in connecting histone modifications with the DNA damage response.

引用

页码：301 / 313

页数：13

共 65 条

[1]

Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks [J].