title: Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression.
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.
authors: Institute for Genetics and CECAD Research Center, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
authors: André
authors: A
authors: Franz
authors: Institute for Genetics and CECAD Research Center, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
authors: Paul A
authors: PA
authors: Pirson
authors: Institute for Genetics and CECAD Research Center, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.|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.
authors: Domenic
authors: D
authors: Pilger
authors: 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.
authors: Swagata
authors: S
authors: Halder
authors: 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.
authors: Divya
authors: D
authors: Achuthankutty
authors: 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.
authors: Hamid
authors: H
authors: Kashkar
authors: 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.
authors: Kristijan
authors: K
authors: Ramadan
authors: Institute for Genetics and CECAD Research Center, University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany.
authors: Thorsten
authors: T
authors: Hoppe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication / Q000235:genetics*; D004625:Embryo, Nonmammalian; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008025:Ligases / Q000378:metabolism*; D008853:Microscopy; D059008:Time-Lapse Imaging; D000074405:Valosin Containing Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; C475683:Cdt-1 protein, C elegans; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; C490780:FAF1 protein, human; C000608562:UBXN-3 protein, C elegans; C000608563:evl-18 protein, C elegans; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein; D008025:Ligases