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The deacetylase SIRT6 promotes the repair of UV-induced DNA damage by targeting DDB2.
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2020-08-13 , 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
Affiliation  

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.

中文翻译:

脱乙酰基酶SIRT6通过靶向DDB2促进紫外线诱导的DNA损伤的修复。

NAD +依赖性脱乙酰基酶和单ADP-核糖基转移酶SIRT6通过促进DNA双链断裂修复来稳定基因组,从而起到抑癌作用。但是,SIRT6是否调节核苷酸切除修复(NER)仍然未知。在这里,我们表明SIRT6被募集到UV诱导的DNA损伤的部位,并刺激了UV诱导的DNA损伤的修复。机理研究进一步表明,SIRT6与引发全局基因组NER(GG-NER)的主要传感器DDB2相互作用,并且在紫外线照射下相互作用增强。在紫外线胁迫下,SIRT6在两个赖氨酸残基K35和K77处使DDB2脱乙酰,然后促进DDB2泛素化和从染色质中分离,从而促进下游信号传导。另外,我们表征了源自黑素瘤患者的几种SIRT6突变。这些SIRT6突变体消除了SIRT6对NER的刺激作用,并由于(i)酶活性的部分丧失(P27S或H50Y),(ii)无意义的突变(R150 *)或(iii)高周转率(G134W)而使基因组不稳定。 )。总体而言,我们证明SIRT6通过使DDB2脱乙酰化来促进NER,从而防止黑色素瘤的发生。
更新日期:2020-09-20
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