Acetylation of WRN Protein Regulates Its Stability by Inhibiting Ubiquitination

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2010 Apr 30

PMID 20428248

Citations 34

Authors

Kai Li

Rui Wang

Enerlyn Lozada

Wei Fan

David K Orren

Jianyuan Luo

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Methodology/principal Finding: 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.

Conclusion/significance: 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.

Citing Articles

Response to Replication Stress and Maintenance of Genome Stability by WRN, the Werner Syndrome Protein.

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Werner Syndrome Protein (WRN) Regulates Cell Proliferation and the Human Papillomavirus 16 Life Cycle during Epithelial Differentiation.

James C, Das D, Morgan E, Otoa R, MacDonald A, Morgan I mSphere. 2020; 5(5).

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