Chromatin-associated Degradation is Defined by UBXN-3/FAF1 to Safeguard DNA Replication Fork Progression

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Feb 5

PMID 26842564

Citations 15

Authors

Andre Franz

Paul A Pirson

Domenic Pilger

Swagata Halder

Divya Achuthankutty

Hamid Kashkar

Kristijan Ramadan

Thorsten Hoppe

Affiliations

Soon will be listed here.

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.

Citing Articles

Sumoylation of SAP130 regulates its interaction with FAF1 as well as its protein stability and transcriptional repressor function.

Chen C, Lin H, Huang M, Chiang C, Lee K, Phuong N BMC Mol Cell Biol. 2024; 25(1):2.

PMID: 38172660 PMC: 10765799. DOI: 10.1186/s12860-023-00498-x.

The FAM104 proteins VCF1/2 promote the nuclear localization of p97/VCP.

Korner M, Meyer S, Marincola G, Kern M, Grimm C, Schuelein-Voelk C Elife. 2023; 12.

PMID: 37713320 PMC: 10541173. DOI: 10.7554/eLife.92409.

TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells.

Scaramuzza S, Jones R, Sadurni M, Reynolds-Winczura A, Poovathumkadavil D, Farrell A Nat Commun. 2023; 14(1):5071.

PMID: 37604812 PMC: 10442450. DOI: 10.1038/s41467-023-40695-y.

Targeting of client proteins to the VCP/p97/Cdc48 unfolding machine.

Meyer H, Boom J Front Mol Biosci. 2023; 10:1142989.

PMID: 36825201 PMC: 9941556. DOI: 10.3389/fmolb.2023.1142989.

Cooperative assembly of p97 complexes involved in replication termination.

Kochenova O, Mukkavalli S, Raman M, Walter J Nat Commun. 2022; 13(1):6591.

PMID: 36329031 PMC: 9633789. DOI: 10.1038/s41467-022-34210-y.

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