Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiates the DNA damage response and repair in humans and mice
- Shenzhen University Health Science Center, China
- Shandong University of Technology, China
- Sun Yat-sen University, China
- Tianjin Medical University Cancer Institute and Hospital, China
Abstract
The DNA damage response (DDR) is a highly orchestrated process but how double-strand DNA breaks (DSBs) are initially recognized is unclear. Here, we show that polymerized SIRT6 deacetylase recognizes DSBs and potentiates the DDR in human and mouse cells. First, SIRT1 deacetylates SIRT6 at residue K33, which is important for SIRT6 polymerization and mobilization toward DSBs. Then, K33-deacetylated SIRT6 anchors to γH2AX, allowing its retention on and subsequent remodeling of local chromatin. We show that a K33R mutation that mimics hypoacetylated SIRT6 can rescue defective DNA repair as a result of SIRT1 deficiency in cultured cells. These data highlight the synergistic action between SIRTs in the spatiotemporal regulation of the DDR and DNA repair in humans and mice.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
National Key R&D Program of China (2017YFA0503900)
- Wei-Guo Zhu
- Baohua Liu
National Natural Science Foundation of China (91849208,81972602,81702909,81871114,81601215)
- Minxian Qian
- Zuojun Liu
- Xiaolong Tang
- Xingzhi Xu
- Baohua Liu
National Natural Science Foundation of Guangdong Province (2015A030308007,2017B030301016)
- Minxian Qian
- Wei-Guo Zhu
- Xingzhi Xu
- Baohua Liu
Shenzhen Science and Technology Innovation Commission (ZDSYS20190902093401689,KQJSCX20180328093403969,JCYJ20180507182044945)
- Baohua Liu
Tianjin Municipal Science Foundation for Youths (18JCQNJC79800)
- Fanbiao Meng
Youth Foundation of Tianjin Medical University Cancer Institute and Hospital (B1714)
- Fanbiao Meng
National Natural Science Foundation of China (91949124)
- Minxian Qian
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Meng et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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