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Quinet, Annabel; Tirman, Stephanie; Jackson, Jessica; Šviković, Saša; Lemaçon, Delphine; Carvajal-Maldonado, Denisse; González-Acosta, Daniel; Vessoni, Alexandre T.; Cybulla, Emily; Wood, Matthew; Tavis, Steven; Batista, Luis F.Z.; Méndez, Juan; Sale, Julian E.; Vindigni, Alessandro
Molecular cell, 02/2020, Volume: 77, Issue: 3Journal Article
Acute treatment with replication-stalling chemotherapeutics causes reversal of replication forks. BRCA proteins protect reversed forks from nucleolytic degradation, and their loss leads to chemosensitivity. Here, we show that fork degradation is no longer detectable in BRCA1-deficient cancer cells exposed to multiple cisplatin doses, mimicking a clinical treatment regimen. This effect depends on increased expression and chromatin loading of PRIMPOL and is regulated by ATR activity. Electron microscopy and single-molecule DNA fiber analyses reveal that PRIMPOL rescues fork degradation by reinitiating DNA synthesis past DNA lesions. PRIMPOL repriming leads to accumulation of ssDNA gaps while suppressing fork reversal. We propose that cells adapt to repeated cisplatin doses by activating PRIMPOL repriming under conditions that would otherwise promote pathological reversed fork degradation. This effect is generalizable to other conditions of impaired fork reversal (e.g., SMARCAL1 loss or PARP inhibition) and suggests a new strategy to modulate cisplatin chemosensitivity by targeting the PRIMPOL pathway. Display omitted •Multiple cisplatin doses suppress reversed fork degradation in BRCA-deficient cells•The PRIMPOL adaptive response suppresses fork reversal and leads to ssDNA gaps•The ATR kinase regulates the PRIMPOL-mediated adaptive response•Impaired fork reversal shifts the balance toward PRIMPOL-mediated repriming Reversed replication forks are degraded in BRCA-deficient cells. Quinet et al. show that treatment with multiple cisplatin doses promotes PRIMPOL repriming while suppressing fork reversal and preventing degradation. These studies identify a new function of PRIMPOL in the replication stress response and explain how cells adapt to multiple drug doses.
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