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

André Franz, Paul A. Pirson, Domenic Pilger, Swagata Halder, Divya Achuthankutty, Hamid Kashkar, Kristijan Ramadan, Thorsten Hoppe*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

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.

Original languageEnglish
Article number10612
JournalNature Communications
Volume7
DOIs
Publication statusPublished - Feb 4 2016
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2016, Nature Publishing Group. All rights reserved.

ASJC Scopus Subject Areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy

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