E4 ligase-specific ubiquitination hubs coordinate DNA double-strand-break repair and apoptosis

Research output: Contribution to journalJournal articleResearchpeer-review

  • Ackermann, Leena
  • Michael Schell
  • Wojciech Pokrzywa
  • Éva Kevei
  • Anton Gartner
  • Björn Schumacher
  • Thorsten Hoppe

Multiple protein ubiquitination events at DNA double-strand breaks (DSBs) regulate damage recognition, signaling and repair. It has remained poorly understood how the repair process of DSBs is coordinated with the apoptotic response. Here, we identified the E4 ubiquitin ligase UFD-2 as a mediator of DNA-damage-induced apoptosis in a genetic screen in Caenorhabditis elegans. We found that, after initiation of homologous recombination by RAD-51, UFD-2 forms foci that contain substrate-processivity factors including the ubiquitin-selective segregase CDC-48 (p97), the deubiquitination enzyme ATX-3 (Ataxin-3) and the proteasome. In the absence of UFD-2, RAD-51 foci persist, and DNA damage-induced apoptosis is prevented. In contrast, UFD-2 foci are retained until recombination intermediates are removed by the Holliday-junction-processing enzymes GEN-1, MUS-81 or XPF-1. Formation of UFD-2 foci also requires proapoptotic CEP-1 (p53) signaling. Our findings establish a central role of UFD-2 in the coordination between the DNA-repair process and the apoptotic response.

Original languageEnglish
JournalNature Structural & Molecular Biology
Volume23
Issue number11
Pages (from-to)995-1002
Number of pages8
ISSN1545-9993
DOIs
Publication statusPublished - 2016
Externally publishedYes

    Research areas

  • Animals, Apoptosis, Caenorhabditis elegans/cytology, Caenorhabditis elegans Proteins/genetics, DNA Breaks, Double-Stranded, DNA Damage, DNA Repair, Gene Deletion, Rad51 Recombinase/metabolism, Ubiquitin-Protein Ligase Complexes/genetics, Ubiquitination

ID: 203248413