title: TRAIP is a PCNA-binding ubiquitin ligase that protects genome stability after replication stress.
abstract: Cellular genomes are highly vulnerable to perturbations to chromosomal DNA replication. Proliferating cell nuclear antigen (PCNA), the processivity factor for DNA replication, plays a central role as a platform for recruitment of genome surveillance and DNA repair factors to replication forks, allowing cells to mitigate the threats to genome stability posed by replication stress. We identify the E3 ubiquitin ligase TRAIP as a new factor at active and stressed replication forks that directly interacts with PCNA via a conserved PCNA-interacting peptide (PIP) box motif. We show that TRAIP promotes ATR-dependent checkpoint signaling in human cells by facilitating the generation of RPA-bound single-stranded DNA regions upon replication stress in a manner that critically requires its E3 ligase activity and is potentiated by the PIP box. Consequently, loss of TRAIP function leads to enhanced chromosomal instability and decreased cell survival after replication stress. These findings establish TRAIP as a PCNA-binding ubiquitin ligase with an important role in protecting genome integrity after obstacles to DNA replication.
authors.affiliation: Ubiquitin Signaling Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Saskia
authors.initials: S
authors.lastname: Hoffmann
authors.affiliation: Ubiquitin Signaling Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Stine
authors.initials: S
authors.lastname: Smedegaard
authors.affiliation: Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Macromolecular Crystallography Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Gulnahar B
authors.initials: GB
authors.lastname: Mortuza
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Räschle
authors.affiliation: Structural Biology Unit, Center for Cooperative Research in Biosciences, 48160 Derio, Bizkaia, Spain.
authors.forename: Alain
authors.initials: A
authors.lastname: Ibañez de Opakua
authors.affiliation: Ubiquitin Signaling Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Oka
authors.affiliation: Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Structural Biology Unit, Center for Cooperative Research in Biosciences, 48160 Derio, Bizkaia, Spain IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Blanco
authors.affiliation: Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.affiliation: Macromolecular Crystallography Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Montoya
authors.affiliation: Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Anja
authors.initials: A
authors.lastname: Groth
authors.affiliation: Ubiquitin Signaling Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Bekker-Jensen
authors.affiliation: Ubiquitin Signaling Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark niels.mailand@cpr.ku.dk.
authors.forename: Niels
authors.initials: N
authors.lastname: Mailand
mesh_terms: D004261:DNA Replication / Q000235:genetics*; D042822:Genomic Instability; D006801:Humans; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D018809:Proliferating Cell Nuclear Antigen; C000607340:TRAIP protein, human; D044767:Ubiquitin-Protein Ligases