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

André Franz, Paul A. Pirson, Domenic Pilger, Swagata Halder, Divya Achuthankutty, Hamid Kashkar, Kristijan Ramadan and Thorsten Hoppe ()
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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
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

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10612

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