Identification of a novel K311 ubiquitination site critical for androgen receptor transcriptional activity

McClurg, U, Cork, DM, Darby, Steven, Ryan-Munden, CA, Nakjang, S, Mendes-Côrtes, L, Treumann, A, Gaughan, L and Robson, CN (2016) Identification of a novel K311 ubiquitination site critical for androgen receptor transcriptional activity. Nucleic Acids Research, 45 (4). pp. 1793-1804. ISSN 0305-1048

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The androgen receptor (AR) is the main driver ofprostate cancer (PC) development and progression,and the primary therapeutic target in PC. To date,two functional ubiquitination sites have been iden-tified on AR, both located in its C-terminal ligandbinding domain (LBD). Recent reports highlight theemergence of AR splice variants lacking the LBD thatcan arise during disease progression and contributeto castrate resistance. Here, we report a novel N-terminal ubiquitination site at lysine 311. Ubiquitina-tion of this site plays a role in AR stability and is crit-ical for its transcriptional activity. Inactivation of thissite causes AR to accumulate on chromatin and inac-tivates its transcriptional function as a consequenceof inability to bind to p300. Additionally, mutation atlysine 311 affects cellular transcriptome altering theexpression of genes involved in chromatin organiza-tion, signaling, adhesion, motility, development andmetabolism. Even though this site is present in clini-cally relevant AR-variants it can only be ubiquitinatedin cells when AR retains LBD suggesting a role for ARC-terminus in E2/E3 substrate recognition. We reportthat as a consequence AR variants lacking the LBDcannot be ubiquitinated in the cellular environmentand their protein turnover must be regulated via analternate pathway.

Item Type: Article
Subjects: Sciences > Biomedical Sciences
Divisions: Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences
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Depositing User: Steven Darby
Date Deposited: 11 Apr 2017 13:52
Last Modified: 06 Feb 2020 14:45
ORCID for Steven Darby: ORCID iD

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