DNA translesion synthesis inhibition

Platinum-based chemotherapeutic agents are used to treat a diverse range of cancers. After activation in the cell, these drugs covalently bind to DNA to form DNA adducts that evoke cell death in cancerous cells. Overtime, cancer cells can develop drug resistance by various mechanisms including an increased tolerance for bypassing DNA adducts formed from reacting with platinum-based drugs. One strategy to combat this resistance is to inhibit the enzymes involved in the replication past these DNA adducts during Translesion DNA synthesis (TLS). Human DNA polymerases η, ζ and κ are especially proficient in TLS past platinum-containing DNA adducts. The goal of this research is to gain mechanistic information on TLS polymerases replicating past platinum-based adducts and design inhibitors that selectively target TLS DNA polymerases. Overall, this work will contribute to a better understanding of molecular mechanisms involved in DNA adduct bypass and help in the development of therapies to mitigate platinum-based drug resistance.