2. Academic Validation
  3. TRAIP is a PCNA-binding ubiquitin ligase that protects genome stability after replication stress

TRAIP is a PCNA-binding ubiquitin ligase that protects genome stability after replication stress

  • J Cell Biol. 2016 Jan 4;212(1):63-75. doi: 10.1083/jcb.201506071.
Saskia Hoffmann 1,  Stine Smedegaard 1,  Kyosuke Nakamura 2,  Gulnahar B Mortuza 3,  Markus Räschle 4,  Alain Ibañez de Opakua 5,  Yasuyoshi Oka 1,  Yunpeng Feng 2,  Francisco J Blanco 6,  Matthias Mann 4,  Guillermo Montoya 3,  Anja Groth 2,  Simon Bekker-Jensen 1,  Niels Mailand 7
Affiliations

Affiliations

  • 1 Ubiquitin Signaling Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
  • 2 Biotech Research and Innovation Center, University of Copenhagen, 2200 Copenhagen, Denmark.
  • 3 Macromolecular Crystallography Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
  • 4 Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
  • 5 Structural Biology Unit, Center for Cooperative Research in Biosciences, 48160 Derio, Bizkaia, Spain.
  • 6 Structural Biology Unit, Center for Cooperative Research in Biosciences, 48160 Derio, Bizkaia, Spain IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain.
  • 7 Ubiquitin Signaling Group, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark [email protected].
PMID: 26711499 DOI: 10.1083/jcb.201506071
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.

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