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

Kai Li, Alex Casta, Rui Wang, Enerlyn Lozada, Wei Fan, Susan Kane, Qingyuan Ge, Wei Gu, David Orren, Jianyuan Luo

Research output: Contribution to journalArticlepeer-review

146 Scopus citations

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.

Original languageEnglish
Pages (from-to)7590-7598
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number12
DOIs
StatePublished - Mar 21 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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