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

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.

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

“…Class I-specific HDACi 4SC-202 globally increases both of H3K27ac and H3K4me3 levels around the TSS of genes, but notably decreases occupancy at proximal regions of TSS of genes such as SMAD family member 6 (SMAD6) and E2F transcription factor 8 (E2F8), which are associated with enhancer deactivation (Mishra et al, 2017). Panobinostat and Jamaladdin et al, 2014Heideman et al, 2013Lin et al, 2019Haberland et al, 2009Boucheron et al, 2014Preglej et al, 2020Montgomery et al, 2007Moresi et al, 2012;Dovey et al, Montgomery et al, 2008Lu et al, 2018Ho et al, 2020Bhaskara et al, 2008Bhaskara et al, 2010;Jiang and Hsieh, 2014Ji et al, 2019Hsu et al, 2015Phelps et al, 2016 Chen Impairs genome stability; embryonic lethality Vaquero et al, 2007;Wang et al, 2008 Represses angiogenesis Potente et al, 2007;Dioum et al, 2009;Lim et al, 2010 Impairs nicotinamide mononucleotide (NMN)-induced amelioration of liver fibrosis and NMN-dependent telomere integrity in premature aging mice Amano et al, 2019 Causes methionine restriction-induced lethality in mouse ESC Tang S. et al, 2017 Impairs myeloid-derived suppressor cells (MDSC) differentiation by disturbing glycolytic pathway Liu et al, 2014 Impairs various DNA repair Cohen et al, 2004;Yuan et al, 2007;Ming et al, 2010;Meng et al, 2020 Inhibits autophagy in MEFs Lee et al, 2008 Causes differentiation defects of mice ESC Tang Induces abnormal mitochondrial physiology, oxidative stress and genomic instability Kim et al, 2010 R...…”

“…Deacetylated SIRT6 at K33 by SIRT1 results in SIRT6 polymerization and deposition at γH2AX foci. Moreover, a SIRT6 K33R hypoacetylation mimic can rescue DNA repair defects in SIRT1-deficient cancer cells (Meng et al, 2020). SIRT7 is also associated with NHEJ, as a Sirt7 deficiency impairs the recruitment of 53BP1 to DSB sites and inhibits NHEJ efficiency (Vazquez et al, 2016).…”

Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia‐reperfusion injury by improving mitochondrial quality control: Role of SIRT6

“…68,69 Interestingly, recent studies have indicated the possible interplay between SIRT6 activity and SIRT1/SIRT3 signaling following cell stress. 70,71 Thus, crosstalk between SIRT6 and other sirtuin family members deserves further study. Additionally, the present study coincides with a recent randomized control trial by Fariba Raygan et al reporting that melatonin intake for 12 weeks to type 2 diabetic patients with coronary heart disease showed beneficial effects on multiple biomarkers of oxidative stress and cardio-metabolic risk.…”

SIRT7 is a deacetylase of N4-acetylcytidine on ribosomal RNA

“…Of note SIRT7 was previously reported to regulate the production of pre-rRNA and small nucleolar RNAs (snoRNAs) through the core components of the U3 snoRNP complex U3-55 k (Chen et al, 2016). We recently found that sirtuin SIRT6 recognizes double strand breaks and potentiates the DNA damage response (Meng et al, 2020). Whether SIRT6 and other sirtuins also deacetylate ac4C merits investigation.…”