Acetylation of WRN Protein Regulates Its Stability by Inhibiting Ubiquitination

• Published in: PloS one Vol. 5; no. 4; p. e10341
• Main Authors: Li, Kai, Wang, Rui, Lozada, Enerlyn, Fan, Wei, Orren, David K., Luo, Jianyuan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.04.2010; Public Library of Science (PLoS)
• Subjects: Acetates; Acetylation; Acetyltransferases - metabolism; Aging; Biochemistry; Biochemistry/ and Repair; Biology; Cancer; Cell Line; Chromatin; CREB-Binding Protein - metabolism; Deacetylation; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Damage; DNA Repair; DNA replication; Enzymatic activity; Enzymes; Event-related potentials; Exodeoxyribonucleases - metabolism; Humans; Lysine; Medical schools; Mitomycin; Mitomycin C; Molecular Biology; Molecular Biology/DNA Repair; Molecular Biology/Post-Translational Regulation of Gene Expression; Mutation; p300-CBP Transcription Factors - metabolism; Protein Processing, Post-Translational; Protein Stability; Proteins; Radioactive half-life; Recombination; RecQ Helicases - metabolism; Residues; Scientific imaging; SIRT1 protein; Stability; Toxicology; Transcription factors; Ubiquitin; Ubiquitination; Werner Syndrome Helicase; WRN protein; United States > US; Massachusetts; Kentucky
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0010341

WRN is a multi-functional protein involving DNA replication, recombination and repair. WRN acetylation has been demonstrated playing an important role in response to DNA damage. We previously found that WRN acetylation can regulate its enzymatic activities and nuclear distribution. Here, we investigated the factors involved in WRN acetylation and found that CBP and p300 are the only major acetyltransferases for WRN acetylation. We further identified 6 lysine residues in WRN that are subject to acetylation. Interestingly, WRN acetylation can increase its protein stability. SIRT1-mediated deacetylation of WRN reverses this effect. CBP dramatically increases the half-life of wild type WRN, while mutation of these 6 lysine residues (WRN-6KR) abrogates this increase. We further found that WRN stability is regulated by the ubiquitination pathway and WRN acetylation by CBP significantly reduces its ubiquitination. Importantly, we found that WRN is strongly acetylated and stabilized in response to mitomycin C (MMC) treatment. H1299 cells stably expressing WRN-6KR, which mimics unacetylated WRN, display significantly higher MMC sensitivity compared with the cells expressing wild-type WRN. Taken together, these data demonstrate that WRN acetylation regulates its stability and has significant implications regarding the role of acetylation on WRN function in response to DNA damage.