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

Nat Commun. 2016 Feb 4;7:10612. doi: 10.1038/ncomms10612.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Adaptor Proteins, Signal Transducing
  • Caenorhabditis elegans Proteins
  • Carrier Proteins
  • Cdt-1 protein, C elegans
  • Cell Cycle Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • FAF1 protein, human
  • UBXN-3 protein, C elegans
  • evl-18 protein, C elegans
  • Adenosine Triphosphatases
  • Valosin Containing Protein
  • Ligases