Acetylation of WRN protein regulates its stability by inhibiting ubiquitination.
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.


RESULTS
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.


CONCLUSIONS
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.
Li
Kai
K
Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Wang
Rui
R
Lozada
Enerlyn
E
Fan
Wei
W
Orren
David K
DK
Luo
Jianyuan
J
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D005090:Exodeoxyribonucleases / Q000378:metabolism*; D006801:Humans; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D053484:RecQ Helicases / Q000378:metabolism*; D054875:Ubiquitination; D000071657:Werner Syndrome Helicase; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D000123:Acetyltransferases; D050882:CREB-Binding Protein; D050880:p300-CBP Transcription Factors; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase