E4 ligase-specific ubiquitination hubs coordinate DNA double-strand-break repair and apoptosis
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E4 ligase-specific ubiquitination hubs coordinate DNA double-strand-break repair and apoptosis. / Ackermann, Leena; Schell, Michael; Pokrzywa, Wojciech; Kevei, Éva; Gartner, Anton; Schumacher, Björn; Hoppe, Thorsten.
In: Nature Structural & Molecular Biology, Vol. 23, No. 11, 2016, p. 995-1002.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - E4 ligase-specific ubiquitination hubs coordinate DNA double-strand-break repair and apoptosis
AU - Ackermann, Leena
AU - Schell, Michael
AU - Pokrzywa, Wojciech
AU - Kevei, Éva
AU - Gartner, Anton
AU - Schumacher, Björn
AU - Hoppe, Thorsten
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Animals
KW - Apoptosis
KW - Caenorhabditis elegans/cytology
KW - Caenorhabditis elegans Proteins/genetics
KW - DNA Breaks, Double-Stranded
KW - DNA Damage
KW - DNA Repair
KW - Gene Deletion
KW - Rad51 Recombinase/metabolism
KW - Ubiquitin-Protein Ligase Complexes/genetics
KW - Ubiquitination
U2 - 10.1038/nsmb.3296
DO - 10.1038/nsmb.3296
M3 - Journal article
C2 - 27669035
VL - 23
SP - 995
EP - 1002
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
SN - 1545-9993
IS - 11
ER -
ID: 203248413