Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 26842564.
- Also identified by DOI 10.1038/ncomms10612 and PMC identifier 4743000.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Adaptor Proteins, Signal Transducing
- Adenosine Triphosphatases
- Caenorhabditis elegans Proteins
- Carrier Proteins
- Cell Cycle Proteins
- Chromatin
- DNA Replication
- Ligases