2. Academic Validation
  3. The deacetylase SIRT6 promotes the repair of UV-induced DNA damage by targeting DDB2

The deacetylase SIRT6 promotes the repair of UV-induced DNA damage by targeting DDB2

  • Nucleic Acids Res. 2020 Sep 18;48(16):9181-9194. doi: 10.1093/nar/gkaa661.
Anke Geng 1,  Huanyin Tang 1,  Jin Huang 2,  Zhen Qian 1,  Nan Qin 1,  Yunxia Yao 1 3,  Zhu Xu 1,  Hao Chen 4,  Li Lan 4,  Hongjuan Xie 1,  Jian Zhang 5,  Ying Jiang 1,  Zhiyong Mao 1 6
Affiliations

Affiliations

  • 1 Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 2 Key Laboratory of Environmental Pollution Monitoring and Disease Control of Ministry of Education, Guizhou Medical University, Guiyang 550025, China.
  • 3 College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
  • 4 University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
  • 5 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiao-Tong University School of Medicine, 200025 Shanghai, China.
  • 6 Tsingtao Advanced Research Institute, Tongji University, 67 Yinchuan West Road, Qingdao 266071, China.
PMID: 32789493 DOI: 10.1093/nar/gkaa661
Abstract

The NAD+-dependent deacetylase and mono-ADP-ribosyl transferase SIRT6 stabilizes the genome by promoting DNA double strand break repair, thereby acting as a tumor suppressor. However, whether SIRT6 regulates nucleotide excision repair (NER) remains unknown. Here, we showed that SIRT6 was recruited to sites of UV-induced DNA damage and stimulated the repair of UV-induced DNA damage. Mechanistic studies further indicated that SIRT6 interacted with DDB2, the major sensor initiating global genome NER (GG-NER), and that the interaction was enhanced upon UV irradiation. SIRT6 deacetylated DDB2 at two lysine residues, K35 and K77, upon UV stress and then promoted DDB2 ubiquitination and segregation from chromatin, thereby facilitating downstream signaling. In addition, we characterized several SIRT6 mutations derived from melanoma patients. These SIRT6 mutants ablated the stimulatory effect of SIRT6 on NER and destabilized the genome due to (i) partial loss of enzymatic activity (P27S or H50Y), (ii) a nonsense mutation (R150*) or (iii) high turnover rates (G134W). Overall, we demonstrate that SIRT6 promotes NER by deacetylating DDB2, thereby preventing the onset of melanomagenesis.

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