Human SIRT6 Promotes DNA End Resection Through CtIP Deacetylation

Science. 2010 Sep 10;329(5997):1348-53. doi: 10.1126/science.1192049.

Abstract

SIRT6 belongs to the sirtuin family of protein lysine deacetylases, which regulate aging and genome stability. We found that human SIRT6 has a role in promoting DNA end resection, a crucial step in DNA double-strand break (DSB) repair by homologous recombination. SIRT6 depletion impaired the accumulation of replication protein A and single-stranded DNA at DNA damage sites, reduced rates of homologous recombination, and sensitized cells to DSB-inducing agents. We identified the DSB resection protein CtIP [C-terminal binding protein (CtBP) interacting protein] as a SIRT6 interaction partner and showed that SIRT6-dependent CtIP deacetylation promotes resection. A nonacetylatable CtIP mutant alleviated the effect of SIRT6 depletion on resection, thus identifying CtIP as a key substrate by which SIRT6 facilitates DSB processing and homologous recombination. These findings further clarify how SIRT6 promotes genome stability.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Acetylation
  • Animals
  • Camptothecin / pharmacology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA / metabolism*
  • DNA Breaks, Double-Stranded*
  • DNA Repair*
  • DNA, Single-Stranded / metabolism
  • Genomic Instability
  • Humans
  • Mice
  • Mutant Proteins / metabolism
  • Niacinamide / pharmacology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Recombination, Genetic / drug effects
  • Sirtuins / genetics
  • Sirtuins / metabolism*

Substances

  • Carrier Proteins
  • DNA, Single-Stranded
  • Mutant Proteins
  • Nuclear Proteins
  • Niacinamide
  • DNA
  • RBBP8 protein, human
  • SIRT6 protein, human
  • Sirtuins
  • Camptothecin