RFWD3/FANCW orchestrates post-replicative filling of ssDNA gaps to promote UV tolerance
Abstract
DNA lesions can stall replication, generating ssDNA gaps that require filling to maintain genome stability. The E3 ubiquitin ligase RFWD3/FANCW targets RPA and PCNA to regulate replication dynamics and damage tolerance, but its roles in these processes and influence on cell mutability remain incompletely understood. Here, we show that RFWD3 prevents the accumulation of ssDNA gaps in UV-irradiated cells through its E3 ligase activity and interaction with RPA. Mutational signature analysis implicates RFWD3 in the spontaneous mutability of human cells and reveals its involvement in 6-4 photoproducts tolerance. Accordingly, photorepair of 6-4 photoproducts, but not of cyclobutane pyrimidine dimers, alleviates gap accumulation in RFWD3-depleted cells. RFWD3 KO has limited impact on PCNA ubiquitylation, but its depletion sharply decreases UV-induced RPA ubiquitylation. Moreover, cells expressing an RPA mutant that cannot be ubiquitylated accumulate ssDNA gaps epistatically with RFWD3 loss. We propose that RFWD3-dependent RPA ubiquitylation regulates post-replicative ssDNA gaps to promote helix-distorting lesion tolerance.
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BibTeX
@article{casimir2026rfwd3fancw,
title = {{RFWD3/FANCW orchestrates post-replicative filling of ssDNA gaps to promote UV tolerance}},
author = {Lisa Casimir and Isabelle Marois and Félix Racine-Brassard and Jean-Christophe Dubois and Félix Goudreau and Maïlyn Yates and Rima Kochman and Billel Djerir and Samuel Zimmer and Yosra Mehrjoo and Alexandra Octaviana Szenti and Vincent Mimee and François Bélanger and Andréanne Blondeau and Gaëlle Lescalet and Edlie St-Hilaire and Wendy Leung and Ryan M. Baxley and Nadia Côté and Luc Gaudreau and Anja Katrin Bielinsky and Laurent Cappadocia and Elliot Drobetsky and Amélie Fradet-Turcotte and Stéphane Coulon and Hugo Wurtele and Pierre-Étienne Jacques and Alexandre Maréchal},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78252-y},
url = {https://www.nature.com/articles/s41467-026-78252-y},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - RFWD3/FANCW orchestrates post-replicative filling of ssDNA gaps to promote UV tolerance
AU - Lisa Casimir
AU - Isabelle Marois
AU - Félix Racine-Brassard
AU - Jean-Christophe Dubois
AU - Félix Goudreau
AU - Maïlyn Yates
AU - Rima Kochman
AU - Billel Djerir
AU - Samuel Zimmer
AU - Yosra Mehrjoo
AU - Alexandra Octaviana Szenti
AU - Vincent Mimee
AU - François Bélanger
AU - Andréanne Blondeau
AU - Gaëlle Lescalet
AU - Edlie St-Hilaire
AU - Wendy Leung
AU - Ryan M. Baxley
AU - Nadia Côté
AU - Luc Gaudreau
AU - Anja Katrin Bielinsky
AU - Laurent Cappadocia
AU - Elliot Drobetsky
AU - Amélie Fradet-Turcotte
AU - Stéphane Coulon
AU - Hugo Wurtele
AU - Pierre-Étienne Jacques
AU - Alexandre Maréchal
PY - 2026
DA - 2026/10/05
JO - Nature Communications
DO - 10.1038/s41467-026-78252-y
UR - https://www.nature.com/articles/s41467-026-78252-y
AB - DNA lesions can stall replication, generating ssDNA gaps that require filling to maintain genome stability. The E3 ubiquitin ligase RFWD3/FANCW targets RPA and PCNA to regulate replication dynamics and damage tolerance, but its roles in these processes and influence on cell mutability remain incompletely understood. Here, we show that RFWD3 prevents the accumulation of ssDNA gaps in UV-irradiated cells through its E3 ligase activity and interaction with RPA. Mutational signature analysis implicates RFWD3 in the spontaneous mutability of human cells and reveals its involvement in 6-4 photoproducts tolerance. Accordingly, photorepair of 6-4 photoproducts, but not of cyclobutane pyrimidine dimers, alleviates gap accumulation in RFWD3-depleted cells. RFWD3 KO has limited impact on PCNA ubiquitylation, but its depletion sharply decreases UV-induced RPA ubiquitylation. Moreover, cells expressing an RPA mutant that cannot be ubiquitylated accumulate ssDNA gaps epistatically with RFWD3 loss. We propose that RFWD3-dependent RPA ubiquitylation regulates post-replicative ssDNA gaps to promote helix-distorting lesion tolerance.
SN - 2041-1723
ER -