Exploiting DNA damage tolerance for precision oncology.

Authors

Audesh Bhat, Ganesh P Lahane, Raj K Pandita, Albino Bacolla, Bettina Hoden, Kenneth S Ramos, Sunil Krishnan, Partha S Sarkar, Arti Dhar, John A Tainer, Tej K Pandita

Published in

Trends in cancer. Sep 05, 2026. Epub Sep 05, 2026.

Abstract

Unresolved DNA lesions trigger replication stress, forcing cancer cells to hijack DNA damage tolerance (DDT) networks, specifically translesion synthesis (TLS) and template switching, to sustain replication. While DDT prevents lethal fork collapse, error-prone TLS drives mutagenesis, tumor evolution, chemoresistance and radioresistance. Proliferating cell nuclear antigen post-translational modifications dynamically govern pathway selection. Cancer cells exploit this plasticity, creating actionable vulnerabilities such as postreplicative single-stranded DNA gaps. Emerging inhibitors targeting TLS polymerases, upstream regulators such as ubiquitin-specific peptidase 1 (USP1), and critical protein-protein interactions offer unprecedented opportunities for precision oncology. By integrating DDT inhibition with biomarkers such as homologous recombination deficiency and tumor mutational burden, we can drive synthetic lethality, sensitize tumors to genotoxic agents, suppress treatment-induced mutagenesis, and potentially enhance responses to immunotherapy.

PMID:
42697814
Bibliographic data and abstract were imported from PubMed on 05 Sep 2026.

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