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Checkpoint-dependent RNR induction promotes fork restart after replicative stress

AuthorsMorafraile, Esther C.; Diffley, John F. X.; Tercero, José Antonio ; Segurado, Mónica
Issue Date20-Jan-2015
PublisherNature Publishing Group
CitationScientific Reports 5: 7886 (2015)
AbstractThe checkpoint kinase Rad53 is crucial to regulate DNA replication in the presence of replicative stress. Under conditions that interfere with the progression of replication forks, Rad53 prevents Exo1-dependent fork degradation. However, although EXO1 deletion avoids fork degradation in rad53 mutants, it does not suppress their sensitivity to the ribonucleotide reductase (RNR) inhibitor hydroxyurea (HU). In this case, the inability to restart stalled forks is likely to account for the lethality of rad53 mutant cells after replication blocks. Here we show that Rad53 regulates replication restart through the checkpoint-dependent transcriptional response, and more specifically, through RNR induction. Thus, in addition to preventing fork degradation, Rad53 prevents cell death in the presence of HU by regulating RNR-expression and localization. When RNR is induced in the absence of Exo1 and RNR negative regulators, cell viability of rad53 mutants treated with HU is increased and the ability of replication forks to restart after replicative stress is restored.
Publisher version (URL)https://doi.org/10.1038/srep07886
Identifiersdoi: 10.1038/srep07886
issn: 2045-2322
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