SIRT6 Recruits SNF2H to DNA Break Sites, Preventing Genomic Instability through Chromatin Remodeling

Abstract

Summary DNA damage is linked to multiple human diseases, such as cancer, neurodegeneration and senescence. Little is known about the role of chromatin accessibility in DNA repair. Here, we find that the histone deacetylase SIRT6 is one of the earliest factors recruited to sites of Double-Strand Breaks (DSBs). SIRT6 recruits the ISWI-chromatin remodeler SNF2H to DSBs, and deacetylates focally histone H3K56. Lack of SIRT6 and SNF2H impairs chromatin remodeling, increasing sensitivity to genotoxic damage and recruitment of downstream factors, such as 53BP1, BRCA1 and RPA. Remarkably, SIRT6 deficient mice exhibit lower levels of chromatin-associated SNF2H in specific tissues, a phenotype accompanied by increased DNA damage. We demonstrate that SIRT6 is critical for recruitment of a chromatin remodeler as an early step in the DNA damage response, indicating that proper unfolding of chromatin plays a rate-limiting role. We present a novel crosstalk between a histone modifier and a chromatin remodeler, regulating a coordinated response to prevent DNA damage.

Chromatin modification and NBS1: their relationship in DNA double-strand break repair

“…We, as well as other groups, reported that the chromatin remodeling factor SNF2h/SMARCA5 is recruited to DSB damage sites induced by laser micro-irradiation (Nakamura et al, 2011;Toiber et al, 2013;Vidi et al, 2014). We also found that depletion of RNF20 reduced H2B ubiquitination-mediated methylation (H3-K4) and accumulation of SNF2h at DSB sites, suggesting that RNF20-dependent ubiquitination of H2B and H3 methylation are crucial for the recruitment of SNF2h to DSB sites.…”

“…Depletion of SUPT16H caused similar defects to those observed in RNF20-deficient cells regarding chromatin accumulation of RNF20, IR-induced focus formation of HR-related factors (BRCA1 and RAD51) and HR activity, suggesting that SUPT16H plays a key role in RNF20-dependent DDRs through its interactions. Depletion of SIRT6, a histone deacetylase, reduced RNF20 recruitment to DSB sites and also H2B K120 ubiquitination (Toiber et al, 2013;Vidi et al, 2014). Accumulation of RNF20 may be regulated by its histone acetylation status as well as its interaction with NBS1 and SNF2h.…”

“…SNF2h can be recruited to DSB sites through its interaction with RNF168, poly-ADPribosylated by PARP1 (Smeenk et al, 2013). The structural nuclear protein NuMA may also contribute to SNF2h accumulation at DSB sites, and SIRT6 has been suggested to participate in the recruitment of SNF2h to chromatin containing DSB damage (Toiber et al, 2013;Vidi et al, 2014). SIRT6-depleted cells decrease SNF2h recruitment to DSB sites, but SIRT6-knockout mouse cells also decrease chromatin association of RNF20 and H2B ubiquitination (Toiber et al, 2013).…”

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

“…Indeed, SIRT1 is an apical effector involved in the stabilization of ATM at DNA breaks, which is essential for DDR propagation (Dobbin et al , 2013). SIRT6 also participates in the early events of DDR, as indicated by its rapid accumulation at DNA damage sites, where it recruits the chromatin remodeler SNF2H and focally deacetylates histones H3K56 (Toiber et al , 2013) and H3K9 (McCord et al , 2009). In addition, SIRT6 depletion impairs the recruitment of downstream effectors from both NHEJ and HR repair pathways to DSB (Kaidi et al , 2010; Toiber et al , 2013).…”

“…SIRT6 also participates in the early events of DDR, as indicated by its rapid accumulation at DNA damage sites, where it recruits the chromatin remodeler SNF2H and focally deacetylates histones H3K56 (Toiber et al , 2013) and H3K9 (McCord et al , 2009). In addition, SIRT6 depletion impairs the recruitment of downstream effectors from both NHEJ and HR repair pathways to DSB (Kaidi et al , 2010; Toiber et al , 2013). Our results indicate that SIRT7 is located downstream of SIRT1 and SIRT6 in the DNA damage signaling cascade.…”