Leveraging the replication stress response to optimize cancer therapy

High-fidelity DNA replication is critical for the faithful transmission of genetic information to daughter cells. Following genotoxic stress, specialized DNA damage tolerance pathways are activated to ensure replication fork progression. These pathways include translesion DNA synthesis, template switching and repriming. In this Review, we describe how DNA damage tolerance pathways impact genome stability, their connection with tumorigenesis and their effects on cancer therapy response. We discuss recent findings that single-strand DNA gap accumulation impacts chemoresponse and explore a growing body of evidence that suggests that different DNA damage tolerance factors, including translesion synthesis polymerases, template switching proteins and enzymes affecting single-stranded DNA gaps, represent useful cancer targets. We further outline how the consequences of DNA damage tolerance mechanisms could inform the discovery of new biomarkers to refine cancer therapies. The activation of DNA damage tolerance (DDT) pathways as part of the replication stress response to DNA damage is key for maintaining genome integrity and, as a result, these pathways are closely linked to tumorigenesis. In this Review, Cybulla and Vindigni discuss the many connections between DDT, replication stress and cancer, detail opportunities for clinical biomarker development, and outline therapeutic strategies for targeting these pathways.