2. Academic Validation
  3. SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair

SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair

  • Sci Adv. 2019 Mar 27;5(3):eaav1118. doi: 10.1126/sciadv.aav1118.
Ming Tang 1 2 3,  Zhiming Li 1 2,  Chaohua Zhang 2,  Xiaopeng Lu 1,  Bo Tu 2,  Ziyang Cao 1 2,  Yinglu Li 1 2,  Yongcan Chen 1 4,  Lu Jiang 2,  Hui Wang 1 2,  Lina Wang 2,  Jiadong Wang 5,  Baohua Liu 1,  Xingzhi Xu 1,  Haiying Wang 2,  Wei-Guo Zhu 1 2 4
Affiliations

Affiliations

  • 1 Guangdong Key Laboratory of Genome Instability and Human Disease, Shenzhen University Carson Cancer Center, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen 518060, China.
  • 2 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function.
  • 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 4 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China.
  • 5 Peking University-Tsinghua University Center for Life Sciences, Beijing 100871, China.
PMID: 30944854 DOI: 10.1126/sciadv.aav1118
Abstract

The activation of ataxia-telangiectasia mutated (ATM) upon DNA damage involves a cascade of reactions, including acetylation by TIP60 and autophosphorylation. However, how ATM is progressively deactivated after completing DNA damage repair remains obscure. Here, we report that Sirtuin 7 (SIRT7)-mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. In response to DNA damage, SIRT7 is mobilized onto chromatin and deacetylates ATM during the late stages of DNA damage response, when ATM is being gradually deactivated. Deacetylation of ATM by SIRT7 is prerequisite for its dephosphorylation by its Phosphatase WIP1. Consequently, depletion of SIRT7 or acetylation-mimic mutation of ATM induces persistent ATM phosphorylation and activation, thus leading to impaired DNA damage repair. Together, our findings reveal a previously unidentified role of SIRT7 in regulating ATM activity and DNA damage repair.

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