Sirt6 recruits SNF2h to sites of damage allowing chromaton remodelling and repair

DEBORAH TOIBER; ERDEL, DM; DM SILBERMAN; LEI ZHONG; MULLIGAN P; BOUAZOUNE K; CARLOS SEBASTIÁN; CLAUDIA COSENTINO; BÁRBARA MARTÍNEZ-PASTOR; AGUSTINA DURSO; NAAR A; KINGSTON R; RIPPE K; RAUL MOSTOSLAVSKY

Banff

Simposio; DNA replication and recombination; 2013

Keystone Symposia on Molecular and Cellular Biology

Efñcient DNA repair plays a critical role in preventing genomic instability, anunderlying mechanism in multiple diseases including cancer. While numerous studies point to a crucial role of chromatin in DNA repair, the molecular factors involved as Well as their interplay remain to be fully characterized. We show here that the histone deacetylase SIRT6 is one of the earliest factor recruited to sites of Double Strand Breaks (DSBS), serving two critical functions: SIRT6 recruits SNFZl-l, a member ofthe ISWI ATP-dependent chromatin remodeling family, and deacetylates histone H3 at lysine K56. Lack ofSIRTó and/or SNFZH im pairs chromatin remodeling and increases sensitivity to genotoxic damage through epistatic pathways. Furthermore, these defects En chromatin remodeling inhibit recruitment of downstream repair factors, such as SBBPi, in turn increasing genomic instability. SIRT6 deficient mice have lower levels of chromatin-associated SNFZH in specific tissues such as brain, a phenotype accompanied by increased signs of DNA damage. Our results demonstrate that SIRT6 plays a critical role in recruiting a chromatin remodeler as an early step in the DNA damage response, indicating that proper unfolding of chromatin plays a rate-Iímiting role in this process.