Mutagenic translesion synthesis (TLS) allows cells to increase their survival after DNA damage by bypassing lesions that normally block DNA replication but at the cost of introducing mutations. Interfering with this TLS pathway genetically or with the small molecule inhibitor JH-RE-06 has been shown to improve cisplatin chemotherapy by suppressing tumor growth and enhancing survival in mouse xenograft tumor models. Deleting Rev7, which is a component of both the TLS machinery and a complex that regulates the choice of double-strand break repair pathways, strikingly potentiates cisplatin chemotherapy in a lung cancer model. Moreover, while cisplatin monotherapy resulted in tumor cell apoptosis, Rev7 deletion promoted a cisplatin-induced senescence phenotype, suggesting that targeting Rev7 is an attractive strategy to improve chemotherapy.
