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Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression

Author

Listed:
  • André Franz

    (Institute for Genetics and CECAD Research Center, University of Cologne)

  • Paul A. Pirson

    (Institute for Genetics and CECAD Research Center, University of Cologne)

  • Domenic Pilger

    (Institute for Genetics and CECAD Research Center, University of Cologne
    University of Oxford, Cancer Research UK/Medical Research Council Oxford, Institute for Radiation Oncology)

  • Swagata Halder

    (University of Oxford, Cancer Research UK/Medical Research Council Oxford, Institute for Radiation Oncology)

  • Divya Achuthankutty

    (University of Oxford, Cancer Research UK/Medical Research Council Oxford, Institute for Radiation Oncology)

  • Hamid Kashkar

    (Centre for Molecular Medicine Cologne and Institute for Medical Microbiology, Immunology and Hygiene at CECAD Research Center, University Hospital of Cologne)

  • Kristijan Ramadan

    (University of Oxford, Cancer Research UK/Medical Research Council Oxford, Institute for Radiation Oncology)

  • Thorsten Hoppe

    (Institute for Genetics and CECAD Research Center, University of Cologne)

Abstract

The coordinated activity of DNA replication factors is a highly dynamic process that involves ubiquitin-dependent regulation. In this context, the ubiquitin-directed ATPase CDC-48/p97 recently emerged as a key regulator of chromatin-associated degradation in several of the DNA metabolic pathways that assure genome integrity. However, the spatiotemporal control of distinct CDC-48/p97 substrates in the chromatin environment remained unclear. Here, we report that progression of the DNA replication fork is coordinated by UBXN-3/FAF1. UBXN-3/FAF1 binds to the licensing factor CDT-1 and additional ubiquitylated proteins, thus promoting CDC-48/p97-dependent turnover and disassembly of DNA replication factor complexes. Consequently, inactivation of UBXN-3/FAF1 stabilizes CDT-1 and CDC-45/GINS on chromatin, causing severe defects in replication fork dynamics accompanied by pronounced replication stress and eventually resulting in genome instability. Our work identifies a critical substrate selection module of CDC-48/p97 required for chromatin-associated protein degradation in both Caenorhabditis elegans and humans, which is relevant to oncogenesis and aging.

Suggested Citation

  • André Franz & Paul A. Pirson & Domenic Pilger & Swagata Halder & Divya Achuthankutty & Hamid Kashkar & Kristijan Ramadan & Thorsten Hoppe, 2016. "Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression," Nature Communications, Nature, vol. 7(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10612
    DOI: 10.1038/ncomms10612
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