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

Publikation: Bidrag til tidsskriftTidsskriftartikel

Saskia Hoffmann, Stine Smedegaard, Kyosuke Nakamura, Gulnahar B Mortuza, Markus Räschle, Alain Ibañez de Opakua, Yasuyoshi Oka, Yunpeng Feng, Francisco J Blanco, Matthias Mann, Guillermo Montoya, Anja Groth, Simon Bekker-Jensen, Niels Mailand

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.

OriginalsprogEngelsk
TidsskriftThe Journal of Cell Biology
Vol/bind212
Tidsskriftsnummer1
Sider (fra-til)63-75
ISSN0021-9525
DOI
StatusUdgivet - 4 jan. 2016

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