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


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.

SUBMITTER: Butler LR 

PROVIDER: S-EPMC3463844 | biostudies-other | 2012 Oct

REPOSITORIES: biostudies-other

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

Butler Laura R LR   Densham Ruth M RM   Jia Junying J   Garvin Alexander J AJ   Stone Helen R HR   Shah Vandna V   Weekes Daniel D   Festy Frederic F   Beesley James J   Morris Joanna R JR  

The EMBO journal 20120821 19


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/  ...[more]

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