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

• Published in: Nature communications Vol. 7; no. 1; pp. 10612 - 15
• Main Authors: Franz, André, Pirson, Paul A., Pilger, Domenic, Halder, Swagata, Achuthankutty, Divya, Kashkar, Hamid, Ramadan, Kristijan, Hoppe, Thorsten
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.02.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/51; 13/89; 14/19; 14/34; 14/35; 38/70; 631/337/100; 631/337/474; 631/337/641/151; 64/11; 82/80; 82/83; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Animals; Apoptosis Regulatory Proteins; Biodegradation; Caenorhabditis elegans; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cancer; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell division; Cell Line, Tumor; Chromatin - metabolism; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Deoxyribonucleic acid; DNA; DNA Replication - genetics; Embryo, Nonmammalian; Genomes; HEK293 Cells; Humanities and Social Sciences; Humans; Immunoprecipitation; Inactivation; Licenses; Ligases - metabolism; Medical research; Metabolism; Microscopy; multidisciplinary; Nematodes; Oncology; Proteins; Science; Science (multidisciplinary); Time-Lapse Imaging; Valosin Containing Protein; Yeast; Germany
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10612

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. Cdc48/p97 is a key component of the ubiquitin-proteasome system, acting as a ubiquitin-directed segregase to regulate multiple cellular functions. Here the authors identify UBXN-3/FAF1 as a crucial regulator of chromatin-associated protein degradation that recruits Cdc48/p97 to DNA replication forks.