The proteasomal de-ubiquitinating enzyme POH1 promotes the double-strand DNA break response

Laura R. Butler, Ruth M. Densham, Junying Jia, Alexander J. Garvin, Helen R. Stone, Vandna Shah, Daniel Weekes, Frederic Festy, James Beesley, Joanna R. Morris

Research output: Contribution to journalArticlepeer-review

118 Citations (Scopus)
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Abstract

The regulation of Ubiquitin (Ub) conjugates generated by the complex network of proteins that promote the mammalian DNA double-strand break (DSB) response is not fully understood. We show here that the Ub protease POH1/rpn11/PSMD14 resident in the 19S proteasome regulatory particle is required for processing poly-Ub formed in the DSB response. Proteasome activity is required to restrict tudor domain-dependent 53BP1 accumulation at sites of DNA damage. This occurs both through antagonism of RNF8/RNF168-mediated lysine 63-linked poly-Ub and through the promotion of JMJD2A retention on chromatin. Consistent with this role POH1 acts in opposition to RNF8/RNF168 to modulate end-joining DNA repair. Additionally, POH1 acts independently of 53BP1 in homologous recombination repair to promote RAD51 loading. Accordingly, POH1-deficient cells are sensitive to DNA damaging agents. These data demonstrate that proteasomal POH1 is a key de-ubiquitinating enzyme that regulates ubiquitin conjugates generated in response to damage and that several aspects of the DSB response are regulated by the proteasome. The EMBO Journal (2012) 31, 3918-3934. doi:10.1038/emboj.2012.232; Published online 21 August 2012

Original languageEnglish
Pages (from-to)3918-3934
Number of pages17
JournalEMBO Journal
Volume31
Issue number19
DOIs
Publication statusPublished - 3 Oct 2012

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