E4 ligase-specific ubiquitination hubs coordinate DNA double-strand-break repair and apoptosis.
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.
Institute for Genetics and CECAD Research Center, University of Cologne, Joseph-Stelzmann Str. 26, 50931 Cologne, Germany.
Leena
L
Ackermann
Institute for Genetics and CECAD Research Center, University of Cologne, Joseph-Stelzmann Str. 26, 50931 Cologne, Germany.
Michael
M
Schell
Institute for Genetics and CECAD Research Center, University of Cologne, Joseph-Stelzmann Str. 26, 50931 Cologne, Germany.
Wojciech
W
Pokrzywa
Institute for Genetics and CECAD Research Center, University of Cologne, Joseph-Stelzmann Str. 26, 50931 Cologne, Germany.
Éva
É
Kevei
Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee Scotland.
Anton
A
Gartner
Institute for Genome Stability in Aging and Disease, Medical Faculty, University of Cologne, Joseph-Stelzmann Str. 26, 50931 Cologne, Germany.|CECAD Research Center and Center for Molecular Medicine Cologne, University of Cologne, Joseph-Stelzmann Str. 26, 50931 Cologne, Germany.
Björn
B
Schumacher
Institute for Genetics and CECAD Research Center, University of Cologne, Joseph-Stelzmann Str. 26, 50931 Cologne, Germany.
Thorsten
T
Hoppe
D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D017353:Gene Deletion; D051135:Rad51 Recombinase / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D029742:Caenorhabditis elegans Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D051135:Rad51 Recombinase; C495148:rad-51 protein, C elegans; C000598850:ufd-2 protein, C elegans
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