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

Mol Cell. 2013 Aug 22;51(4):454-68. doi: 10.1016/j.molcel.2013.06.018. Epub 2013 Aug 1.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism
  • Chromatin / genetics*
  • Chromatin Assembly and Disassembly*
  • Chromatin Immunoprecipitation
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA Damage / genetics*
  • DNA Repair / genetics*
  • Genomic Instability*
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Histones / metabolism
  • Humans
  • Immunoprecipitation
  • Mice
  • Mice, Knockout
  • Nucleosomes / metabolism
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Sirtuins / physiology*
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Substances

  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Histones
  • Nucleosomes
  • Sirt6 protein, mouse
  • SIRT6 protein, human
  • Sirtuins
  • Adenosine Triphosphatases
  • SMARCA5 protein, human