Translesion synthesis is a fundamental cellular defense mechanism that enables DNA replication across lesion sites in order to promote cell survival at the cost of replication fidelity. Such a process directly contributes to cancer cell survival and the development of cancer drug resistance after chemotherapy. The eukaryotic Y-family polymerase Rev1 is an essential scaffolding protein in translesion synthesis, and its C-terminal domain (CTD), which interacts with translesion polymerases ?, ?, ? and ?, is absoltely required for function. Recent biochemical and structural investigations have revealed the molecular basis of the Rev1 CTD-mediated assembly of translesion polymerase complexes, and in vivo studies using murine cancer models have established Rev1-mediated translesion synthesis as a promising new target for treatment of drug-resistant tumors. The goal of this proposal is to develop small molecule antagonists of the Rev1 CTD as novel adjuvant cancer therapeutics to enhance the effectiveness of DNA-damaging agents against drug-resistant cancers. This will be achieved by discovery, optimization, and characterization of lead compounds that disrupt the essential scaffolding function of the Rev1 CTD in translesion synthesis and by demonstrating their ability to sensitize drug-resistant cancers to DNA-damaging chemotherapeutics, such as cisplatin.
Chemotherapy with DNA-damaging agents, such as cisplatin, is the cornerstone of treatment for a variety of cancers. Although initial drug responsiveness is typically high, the development of chemoresistance in cancer cells presents a major challenge for successful therapy, and the majority of cancer patients will eventually relapse with drug-resistant, untreatable cancer cell populations. Recent studies have demonstrated an important role of Rev1-dependent translesion synthesis in promoting cancer cell survival and in developing cancer drug resistance after chemotherapy. Since the scaffolding function of the C-terminal domain (CTD) of Rev1 is absolutely required for active translesion synthesis, our efforts to develop small molecule antagonists of the Rev1 CTD will ultimately lead to the development of successful adjuvant cancer therapeutics that disrupt translesion synthesis. Such compounds are expected to sensitize drug-resistant cancer cells to chemotherapy and thwart the emergence of cancer drug resistance, thus improving the clinical outcome of existing DNA-targeting chemotherapeutics for cancer patients.