Identification of Translesion Synthesis Inhibitors that Target Rev7/Rev3 Protein-Protein Interactions
Date of Completion
Dr. Kyle Hadden; Dr. Ashis Basu; Dr. Charles Giardina
University Scholar Major
Molecular and Cell Biology
Medicinal Chemistry and Pharmaceutics
Translesion synthesis (TLS) is a cellular mechanism utilized by cancer cells to tolerate DNA damage caused by chemotherapeutics, like cisplatin, by replicating past unrepaired lesions. This increases the rate of mutations, which leads to the emergence of drug-resistant cancer cells. Preliminary studies have shown that disrupting the protein-protein interactions (PPI) in the TLS heteroprotein complex increases cells’ sensitivity to first-line genotoxic chemotherapy, illustrating how inhibiting TLS assembly and function can significantly increase cancer cell death. These results underscore the therapeutic potential of targeting TLS PPI. My thesis focuses on identifying inhibitors capable of disrupting the Rev7/Rev3 TLS PPI. This study identified three promising inhibitors that disrupt the Rev7/Rev3 PPI with verification of TLS inhibition through biochemical and cellular studies. Future research can optimize these inhibitors to develop a new class of anti-cancer agents that can enhance the efficacy of other drugs and treatments that exert their effects through DNA damage.
Patel, Seema, "Identification of Translesion Synthesis Inhibitors that Target Rev7/Rev3 Protein-Protein Interactions" (2022). University Scholar Projects. 83.