title: SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling.
abstract: DNA damage is linked to multiple human diseases, such as cancer, neurodegeneration, and aging. Little is known about the role of chromatin accessibility in DNA repair. Here, we find that the deacetylase sirtuin 6 (SIRT6) is one of the earliest factors recruited to double-strand breaks (DSBs). SIRT6 recruits the chromatin remodeler SNF2H to DSBs and focally deacetylates histone H3K56. Lack of SIRT6 and SNF2H impairs chromatin remodeling, increasing sensitivity to genotoxic damage and recruitment of downstream factors such as 53BP1 and breast cancer 1 (BRCA1). Remarkably, SIRT6-deficient mice exhibit lower levels of chromatin-associated SNF2H in specific tissues, a phenotype accompanied by 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 unique crosstalk between a histone modifier and a chromatin remodeler, regulating a coordinated response to prevent DNA damage.
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Toiber
authors.forename: Fabian
authors.initials: F
authors.lastname: Erdel
authors.forename: Karim
authors.initials: K
authors.lastname: Bouazoune
authors.forename: Dafne M
authors.initials: DM
authors.lastname: Silberman
authors.forename: Lei
authors.initials: L
authors.lastname: Zhong
authors.forename: Peter
authors.initials: P
authors.lastname: Mulligan
authors.forename: Carlos
authors.initials: C
authors.lastname: Sebastian
authors.forename: Claudia
authors.initials: C
authors.lastname: Cosentino
authors.forename: Barbara
authors.initials: B
authors.lastname: Martinez-Pastor
authors.forename: Sofia
authors.initials: S
authors.lastname: Giacosa
authors.forename: Agustina
authors.initials: A
authors.lastname: D'Urso
authors.forename: Anders M
authors.initials: AM
authors.lastname: Näär
authors.forename: Robert
authors.initials: R
authors.lastname: Kingston
authors.forename: Karsten
authors.initials: K
authors.lastname: Rippe
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D002843:Chromatin / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D042822:Genomic Instability; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009707:Nucleosomes / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D009707:Nucleosomes; C501860:Sirt6 protein, mouse; C516592:SIRT6 protein, human; D037761:Sirtuins; D000251:Adenosine Triphosphatases; C409462:SMARCA5 protein, human
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