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Leveraging the replication stress response to optimize cancer therapy

Nature Reviews Cancer volume 23, pages 6–24 (2023)Cite this article

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Abstract

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.

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Fig. 1: Major mediators of the replication stress response.
Fig. 2: The replication stress response in cancer and emerging therapeutic targets.
Fig. 3: Chemotherapy and PARPi in BRCA-deficient cancers.
Fig. 4: The replication stress response in cancer and implications for cancer biomarkers.

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Acknowledgements

The authors would like to thank L. Zou, P. Verma and J. Eissenberg for their careful reading of this manuscript and for their insightful feedback, and A. Meroni for comments on the figures. This work was supported by the National Cancer Institute (NCI) grants F30CA254215 to E.C. and R01CA237263 and R01CA248526 to A.V.; the US Department of Defense (DOD) Breast Cancer Research Program (BRCP) Expansion Award BC191374 to A.V.; the Alvin J. Siteman Cancer Center Siteman Investment Program (supported by The Foundation for Barnes-Jewish Hospital, Cancer Frontier Fund) to A.V.; and the Barnard Foundation to A.V.

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Authors and Affiliations

  1. Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA

    Emily Cybulla & Alessandro Vindigni

  2. Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA

    Emily Cybulla

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Glossary

DNA lesions

Modifications introduced on the DNA helix by different genotoxic agents.

Xeroderma pigmentosum

An autosomal recessive genetic disease caused by biallelic mutations of specific proteins that are involved in molecular mechanisms required to cope with UV-induced DNA lesions, including Polη.

Polar pausing

Transient pausing of the replication fork in response to a unidirectional barrier that only inhibits replication fork progression in one direction.

Schimke immuno-osseous dysplasia

A multi-system autosomal recessive genetic disease caused by inheritance of biallelic SMARCAL1 mutations, with renal disease being a major cause of mortality in patients with this disease.

RECON syndrome

An autosomal recessive genetic disease caused by biallelic mutations in the RECQL1 DNA helicase, which functions in the DNA damage response.

Microhomology-mediated end joining

(MMEJ). One of the DNA double-strand break repair pathways, along with homologous recombination and non-homologous end joining, which relies on microhomology sequences (1–16 nucleotides) to anneal and align double-strand break ends for repair.

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Cybulla, E., Vindigni, A. Leveraging the replication stress response to optimize cancer therapy. Nat Rev Cancer 23, 6–24 (2023). https://doi.org/10.1038/s41568-022-00518-6

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