SMARCAL1 ubiquitylation controls its association with RPA-coated ssDNA and promotes replication fork stability

Impediments in replication fork progression cause genomic instability, mutagenesis, and severe pathologies. At stalled forks, RPA-coated single-stranded DNA (ssDNA) activates the ATR kinase and directs fork remodeling, 2 key early events of the replication stress response. RFWD3, a recently describe...

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Published in:PLoS biology 2024-03, Vol.22 (3), p.e3002552-e3002552
Main Authors: Yates, Maïlyn, Marois, Isabelle, St-Hilaire, Edlie, Ronato, Daryl A, Djerir, Billel, Brochu, Chloé, Morin, Théo, Hammond-Martel, Ian, Gezzar-Dandashi, Sari, Casimir, Lisa, Drobetsky, Elliot, Cappadocia, Laurent, Masson, Jean-Yves, Wurtele, Hugo, Maréchal, Alexandre
Format: Article
Language:English
Subjects:
Analysis
Anemia
Biology and life sciences
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA damage
DNA repair
DNA replication
Enzymes
Fanconi syndrome
Genomes
Genomic instability
Homologous recombination
Identification and classification
Irradiation
Kinases
Ligases
Mass spectrometry
Medicine and Health Sciences
Mutagenesis
Mutation
Properties
Proteasomes
Proteins
Proteomics
Recruitment
Replication
Replication forks
Research and Analysis Methods
Scientific imaging
Single-stranded DNA
Stability
Substrates
Translocase
Ubiquitin-proteasome system
Ubiquitin-protein ligase
Ultraviolet radiation
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cited_by cdi_FETCH-LOGICAL-c696t-c7e4504f44acff8ce5540fd7063a04579340da44e71968e9f230c6b9b4b0e2873
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creator Yates, Maïlyn
Marois, Isabelle
St-Hilaire, Edlie
Ronato, Daryl A
Djerir, Billel
Brochu, Chloé
Morin, Théo
Hammond-Martel, Ian
Gezzar-Dandashi, Sari
Casimir, Lisa
Drobetsky, Elliot
Cappadocia, Laurent
Masson, Jean-Yves
Wurtele, Hugo
Maréchal, Alexandre
description Impediments in replication fork progression cause genomic instability, mutagenesis, and severe pathologies. At stalled forks, RPA-coated single-stranded DNA (ssDNA) activates the ATR kinase and directs fork remodeling, 2 key early events of the replication stress response. RFWD3, a recently described Fanconi anemia (FA) ubiquitin ligase, associates with RPA and promotes its ubiquitylation, facilitating late steps of homologous recombination (HR). Intriguingly, RFWD3 also regulates fork progression, restart and stability via poorly understood mechanisms. Here, we used proteomics to identify putative RFWD3 substrates during replication stress in human cells. We show that RFWD3 interacts with and ubiquitylates the SMARCAL1 DNA translocase directly in vitro and following DNA damage in vivo. SMARCAL1 ubiquitylation does not trigger its subsequent proteasomal degradation but instead disengages it from RPA thereby regulating its function at replication forks. Proper regulation of SMARCAL1 by RFWD3 at stalled forks protects them from excessive MUS81-mediated cleavage in response to UV irradiation, thereby limiting DNA replication stress. Collectively, our results identify RFWD3-mediated SMARCAL1 ubiquitylation as a novel mechanism that modulates fork remodeling to avoid genome instability triggered by aberrant fork processing.
doi_str_mv 10.1371/journal.pbio.3002552
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ispartof PLoS biology, 2024-03, Vol.22 (3), p.e3002552-e3002552
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subjects Analysis
Anemia
Biology and life sciences
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA damage
DNA repair
DNA replication
Enzymes
Fanconi syndrome
Genomes
Genomic instability
Homologous recombination
Identification and classification
Irradiation
Kinases
Ligases
Mass spectrometry
Medicine and Health Sciences
Mutagenesis
Mutation
Properties
Proteasomes
Proteins
Proteomics
Recruitment
Replication
Replication forks
Research and Analysis Methods
Scientific imaging
Single-stranded DNA
Stability
Substrates
Translocase
Ubiquitin-proteasome system
Ubiquitin-protein ligase
Ultraviolet radiation
title SMARCAL1 ubiquitylation controls its association with RPA-coated ssDNA and promotes replication fork stability
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