Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1

Shinichiro Nakada, Ikue Tai, Stephanie Panier, Abdallah Al-Hakim, Shun Ichiro Iemura, Yu Chi Juang, Lara O'Donnell, Ayako Kumakubo, Meagan Munro, Frank Sicheri, Anne Claude Gingras, Tohru Natsume, Toshio Suda, Daniel Durocher

研究成果: Article

223 引用 (Scopus)

抜粋

DNA double-strand breaks (DSBs) pose a potent threat to genome integrity. These lesions also contribute to the efficacy of radiotherapy and many cancer chemotherapeutics. DSBs elicit a signalling cascade that modifies the chromatin surrounding the break, first by ATM-dependent phosphorylation and then by RNF8-, RNF168- and BRCA1-dependent regulatory ubiquitination. Here we report that OTUB1, a deubiquitinating enzyme, is an inhibitor of DSB-induced chromatin ubiquitination. Surprisingly, we found that OTUB1 suppresses RNF168-dependent poly-ubiquitination independently of its catalytic activity. OTUB1 does so by binding to and inhibiting UBC13 (also known as UBE2N), the cognate E2 enzyme for RNF168. This unusual mode of regulation is unlikely to be limited to UBC13 because analysis of OTUB1-associated proteins revealed that OTUB1 binds to E2s of the UBE2D and UBE2E subfamilies. Finally, OTUB1 depletion mitigates the DSB repair defect associated with defective ATM signalling, indicating that pharmacological targeting of the OTUB1-UBC13 interaction might enhance the DNA damage response.

元の言語English
ページ(範囲)941-946
ページ数6
ジャーナルNature
466
発行部数7309
DOI
出版物ステータスPublished - 2010 8 19

ASJC Scopus subject areas

  • General

フィンガープリント Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1' の研究トピックを掘り下げます。これらはともに一意のフィンガープリントを構成します。

  • これを引用

    Nakada, S., Tai, I., Panier, S., Al-Hakim, A., Iemura, S. I., Juang, Y. C., O'Donnell, L., Kumakubo, A., Munro, M., Sicheri, F., Gingras, A. C., Natsume, T., Suda, T., & Durocher, D. (2010). Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature, 466(7309), 941-946. https://doi.org/10.1038/nature09297