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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.

Original publication




Journal article


Nat Commun

Publication Date





Adaptor Proteins, Signal Transducing, Adenosine Triphosphatases, Animals, Apoptosis Regulatory Proteins, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Carrier Proteins, Cell Cycle Proteins, Cell Line, Tumor, Chromatin, Chromosomal Proteins, Non-Histone, DNA Replication, Embryo, Nonmammalian, HEK293 Cells, Humans, Immunoprecipitation, Ligases, Microscopy, Time-Lapse Imaging, Valosin Containing Protein