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

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118 Citations (Scopus)
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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
Issue number19
Publication statusPublished - 3 Oct 2012


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