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

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

  • Nat Commun. 2016 Feb 4;7:10612. doi: 10.1038/ncomms10612.
André Franz 1,  Paul A Pirson 1,  Domenic Pilger 1 2,  Swagata Halder 2,  Divya Achuthankutty 2,  Hamid Kashkar 3,  Kristijan Ramadan 2,  Thorsten Hoppe 1
Affiliations

Affiliations

  • 1 Institute for Genetics and CECAD Research Center, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
  • 2 Department of Oncology, University of Oxford, Cancer Research UK/Medical Research Council Oxford, Institute for Radiation Oncology, Old Road Campus Research Building, OX3 7DQ Oxford, UK.
  • 3 Centre for Molecular Medicine Cologne and Institute for Medical Microbiology, Immunology and Hygiene at CECAD Research Center, University Hospital of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
PMID: 26842564 DOI: 10.1038/ncomms10612
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.

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