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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

DOI

10.1038/ncomms10612

Type

Journal article

Journal

Nat Commun

Publication Date

04/02/2016

Volume

7

Keywords

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