Fine-Tuning of DNA Damage-Dependent Ubiquitination by OTUB2 Supports the DNA Repair Pathway Choice

Kiyoko Kato, Kazuhiro Nakajima, Ayako Ui, Yuri Muto-Terao, Hideaki Ogiwara, Shinichiro Nakada

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)

Abstract

DNA double-strand breaks (DSBs) are deleterious lesions that lead to genetic mutations and cell death. Protein ubiquitination mediated by the E3 ubiquitin ligase RNF8 within the regions surrounding DSBs recruits DNA DSB response (DDR) factors and induces chromatin remodeling, which supports cell survival after DNA damage. Nevertheless, the impact of RNF8-mediated ubiquitination on DNA repair remains to be elucidated. Here, we report that depletion of the deubiquitinating enzyme OTUB2 enhances RNF8-mediated ubiquitination in an early phase of the DDR and promotes faster DSB repair but suppresses homologous recombination. The rapid ubiquitination results in accelerated accumulation of 53BP1 and RAP80 at DSBs, whichin turn protects DSB ends from resection in OTUB2-depleted cells. Mechanistically, OTUB2 suppresses RNF8-mediated L3MBTL1 ubiquitination and Lys 63-linked ubiquitin chain formation in a deubiquitinating activity-dependent manner. Thus, OTUB2 fine-tunes the speed of DSB-induced ubiquitination so that the appropriate DNA repair pathway is chosen.

Original languageEnglish
Pages (from-to)617-630
Number of pages14
JournalMolecular Cell
Volume53
Issue number4
DOIs
Publication statusPublished - 2014 Feb 20

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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