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

Nat Struct Mol Biol. 2016 Nov;23(11):995-1002. doi: 10.1038/nsmb.3296. Epub 2016 Sep 26.

Abstract

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.

MeSH terms

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

Substances

  • Caenorhabditis elegans Proteins
  • Ubiquitin-Protein Ligase Complexes
  • Rad51 Recombinase
  • rad-51 protein, C elegans
  • ufd-2 protein, C elegans