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

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 - 2016/11/1

Y1 - 2016/11/1

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

SN - 1545-9993

VL - 23

SP - 995

EP - 1002

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 11

ER -