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

TY - JOUR

T1 - The proteasomal de-ubiquitinating enzyme POH1 promotes the double-strand DNA break response

AU - Butler, Laura R.

AU - Densham, Ruth M.

AU - Jia, Junying

AU - Garvin, Alexander J.

AU - Stone, Helen R.

AU - Shah, Vandna

AU - Weekes, Daniel

AU - Festy, Frederic

AU - Beesley, James

AU - Morris, Joanna R.

PY - 2012/10/3

Y1 - 2012/10/3

N2 - 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

AB - 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

U2 - 10.1038/emboj.2012.232

DO - 10.1038/emboj.2012.232

M3 - Article

SN - 0261-4189

VL - 31

SP - 3918

EP - 3934

JO - EMBO Journal

JF - EMBO Journal

IS - 19

ER -