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SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling

Debra Toiber1, Fabian Erdel, Karim Bouazoune

  • 1The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.

Molecular Cell
|August 6, 2013
PubMed

Insights

The deacetylase SIRT6 is crucial for DNA repair, recruiting the chromatin remodeler SNF2H to double-strand breaks (DSBs). This interaction is vital for preventing DNA damage and associated diseases like cancer.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • DNA damage is implicated in numerous human diseases, including cancer, neurodegeneration, and aging.
  • The role of chromatin accessibility in DNA repair mechanisms remains largely unexplored.

Purpose of the Study:

  • To investigate the function of sirtuin 6 (SIRT6) in the early stages of the DNA damage response.
  • To elucidate the relationship between chromatin remodeling and DNA repair pathways.

Main Methods:

  • Identifying early factors recruited to double-strand breaks (DSBs).
  • Analyzing the recruitment of SIRT6 and SNF2H to DSBs.
  • Assessing the impact of SIRT6 and SNF2H deficiency on chromatin remodeling and DNA repair.
  • Investigating SIRT6-deficient mice for DNA damage phenotypes.

Main Results:

  • SIRT6 is an early responder to DSBs, recruiting the chromatin remodeler SNF2H.
  • SIRT6 facilitates focal deacetylation of histone H3K56.
  • Deficiency in SIRT6 or SNF2H impairs chromatin remodeling, heightens sensitivity to genotoxic damage, and affects the recruitment of 53BP1 and BRCA1.
  • SIRT6-deficient mice display reduced chromatin-associated SNF2H and increased DNA damage in specific tissues.

Conclusions:

  • SIRT6 is essential for recruiting chromatin remodelers as an initial step in DNA damage response.
  • Chromatin unfolding is a rate-limiting factor in DNA repair.
  • A novel crosstalk between histone modifiers (SIRT6) and chromatin remodelers (SNF2H) regulates DNA damage response.

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