Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation

J Biol Chem. 2008 Mar 21;283(12):7590-8. doi: 10.1074/jbc.M709707200. Epub 2008 Jan 17.

Abstract

Werner syndrome is an autosomal recessive disorder associated with premature aging and cancer predisposition caused by mutations of the WRN gene. WRN is a member of the RecQ DNA helicase family with functions in maintaining genome stability. Sir2, an NAD-dependent histone deacetylase, has been proven to extend life span in yeast and Caenorhabditis elegans. Mammalian Sir2 (SIRT1) has also been found to regulate premature cellular senescence induced by the tumor suppressors PML and p53. SIRT1 plays an important role in cell survival promoted by calorie restriction. Here we show that SIRT1 interacts with WRN both in vitro and in vivo; this interaction is enhanced after DNA damage. WRN can be acetylated by acetyltransferase CBP/p300, and SIRT1 can deacetylate WRN both in vitro and in vivo. WRN acetylation decreases its helicase and exonuclease activities, and SIRT1 can reverse this effect. WRN acetylation alters its nuclear distribution. Down-regulation of SIRT1 reduces WRN translocation from nucleoplasm to nucleoli after DNA damage. These results suggest that SIRT1 regulates WRN-mediated cellular responses to DNA damage through deacetylation of WRN.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Aging, Premature / genetics
  • Aging, Premature / metabolism
  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism
  • Cell Line
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Cellular Senescence / physiology
  • DNA Damage / physiology
  • Down-Regulation / physiology
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism
  • Exodeoxyribonucleases / genetics
  • Exodeoxyribonucleases / metabolism*
  • Genomic Instability / physiology
  • Humans
  • Longevity / physiology
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Promyelocytic Leukemia Protein
  • RecQ Helicases / genetics
  • RecQ Helicases / metabolism*
  • Sirtuin 1
  • Sirtuins / genetics
  • Sirtuins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Werner Syndrome Helicase

Substances

  • Neoplasm Proteins
  • Nuclear Proteins
  • Promyelocytic Leukemia Protein
  • TP53 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • PML protein, human
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • Exodeoxyribonucleases
  • SIRT1 protein, human
  • Sirtuin 1
  • Sirtuins
  • RecQ Helicases
  • WRN protein, human
  • Werner Syndrome Helicase