Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiates the DNA damage response and repair in humans and mice.

ELife
Fanbiao MengBaohua Liu

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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Methods Mentioned

BETA
pulldown
FACS
co-immunoprecipitation
acetylation
Fluorescence
confocal microscopy
ChIP-PCR
Fluorescence imaging
Co-IP
immunoprecipitation

Software Mentioned

Fiji J
AutoDock Vina
Fiji ( Image J )
Image J
Fiji Image J

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