SIRT2 promotes base excision repair by transcriptionally activating OGG1 in an ATM/ATR-dependent manner

Sirtuin 2 (SIRT2) regulates the maintenance of genome integrity by targeting pathways of DNA damage response and homologous recombination repair. However, whether and how SIRT2 promotes base excision repair (BER) remain to be determined. Here, we found that independent of its catalytic activity SIRT...

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Published in:Nucleic acids research 2024-05, Vol.52 (9), p.5107-5120
Main Authors: Geng, Anke, Sun, Jiahui, Tang, Huanyin, Yu, Yang, Wang, Xiyue, Zhang, Jingyuan, Wang, Xiaona, Sun, Xiaoxiang, Zhou, Xiaofang, Gao, Neng, Tan, Rong, Xu, Zhu, Jiang, Ying, Mao, Zhiyong
Format: Article
Language:English
Subjects:
Ataxia Telangiectasia Mutated Proteins - genetics
Ataxia Telangiectasia Mutated Proteins - metabolism
Cell Line, Tumor
DNA Damage
DNA Glycosylases - genetics
DNA Glycosylases - metabolism
DNA Repair
Excision Repair
Genome Integrity, Repair and
HEK293 Cells
Humans
Oxidative Stress
Phosphorylation
Promoter Regions, Genetic
Sirtuin 2 - genetics
Sirtuin 2 - metabolism
Transcription, Genetic
Transcriptional Activation
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Summary:Sirtuin 2 (SIRT2) regulates the maintenance of genome integrity by targeting pathways of DNA damage response and homologous recombination repair. However, whether and how SIRT2 promotes base excision repair (BER) remain to be determined. Here, we found that independent of its catalytic activity SIRT2 interacted with the critical glycosylase OGG1 to promote OGG1 recruitment to its own promoter upon oxidative stress, thereby enhancing OGG1 promoter activity and increasing BER efficiency. Further studies revealed that SIRT2 was phosphorylated on S46 and S53 by ATM/ATR upon oxidative stress, and SIRT2 phosphorylation enhanced the SIRT2-OGG1 interaction and mediated the stimulatory effect of SIRT2 on OGG1 promoter activity. We also characterized 37 cancer-derived SIRT2 mutants and found that 5 exhibited the loss of the stimulatory effects on OGG1 transcription. Together, our data reveal that SIRT2 acts as a tumor suppressor by promoting OGG1 transcription and increasing BER efficiency in an ATM/ATR-dependent manner.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkae190