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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Adenosine Triphosphatases / genetics*
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Adenosine Triphosphatases / metabolism
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Animals
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Apoptosis Regulatory Proteins
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Caenorhabditis elegans
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Caenorhabditis elegans Proteins / genetics*
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Caenorhabditis elegans Proteins / metabolism
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Cell Cycle Proteins / genetics*
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Chromatin / metabolism*
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Chromosomal Proteins, Non-Histone / genetics
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Chromosomal Proteins, Non-Histone / metabolism
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DNA Replication / genetics*
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Embryo, Nonmammalian
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HEK293 Cells
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Humans
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Immunoprecipitation
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Ligases / metabolism*
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Microscopy
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Time-Lapse Imaging
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Valosin Containing Protein
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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Caenorhabditis elegans Proteins
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Carrier Proteins
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Cdt-1 protein, C elegans
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Cell Cycle Proteins
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Chromatin
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Chromosomal Proteins, Non-Histone
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FAF1 protein, human
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UBXN-3 protein, C elegans
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evl-18 protein, C elegans
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Adenosine Triphosphatases
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Valosin Containing Protein
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Ligases