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

Leena Ackermann, Michael Schell, Wojciech Pokrzywa, Éva Kevei, Anton Gartner, Björn Schumacher (Lead / Corresponding author), Thorsten Hoppe (Lead / Corresponding author)

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    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
    Pages (from-to)995-1002
    Number of pages8
    JournalNature Structural & Molecular Biology
    Issue number11
    Early online date26 Sept 2016
    Publication statusPublished - Nov 2016


    • Apoptosis
    • DNA damage response
    • Double-strand DNA breaks
    • Ubiquitin ligases
    • Ubiquitylation


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