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The proteasomal de-ubiquitinating enzyme POH1 promotes the double-strand DNA break response.
Butler, Laura R; Densham, Ruth M; Jia, Junying; Garvin, Alexander J; Stone, Helen R; Shah, Vandna; Weekes, Daniel; Festy, Frederic; Beesley, James; Morris, Joanna R.
Afiliação
  • Butler LR; School of Cancer Sciences, College of Medical & Dental Sciences, University of Birmingham, Birmingham, UK.
EMBO J ; 31(19): 3918-34, 2012 Oct 03.
Article em En | MEDLINE | ID: mdl-22909820
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transativadores / Complexo de Endopeptidases do Proteassoma / Reparo do DNA / Quebras de DNA de Cadeia Dupla Limite: Humans Idioma: En Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transativadores / Complexo de Endopeptidases do Proteassoma / Reparo do DNA / Quebras de DNA de Cadeia Dupla Limite: Humans Idioma: En Ano de publicação: 2012 Tipo de documento: Article