Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation.
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.
Li
Kai
K
Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Casta
Alex
A
Wang
Rui
R
Lozada
Enerlyn
E
Fan
Wei
W
Kane
Susan
S
Ge
Qingyuan
Q
Gu
Wei
W
Orren
David
D
Luo
Jianyuan
J
D000107:Acetylation; D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D016922:Cellular Senescence / Q000502:physiology; D004249:DNA Damage / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D042822:Genomic Instability / Q000502:physiology; D006801:Humans; D008136:Longevity / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000071657:Werner Syndrome Helicase
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D005090:Exodeoxyribonucleases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase