Madeline Moradi, Pacific University

Abstract:

Gemcitabine (GemC) and Cytarabine (AraC) are common chemotherapy drugs that act as chain terminators to inhibit DNA synthesis. However, in the presence of repair polymerase, Pol η, synthesis proceeds. To combat this, GemC/AraC are administered in high doses, inducing toxic side effects. Previous studies have provided only a static kinetic analysis of GemC/AraC binding, leaving little information regarding their mechanism for inhibition of DNA elongation. We propose the application of both single-base replacement kinetic assays and time-resolved X-ray crystallography to capture the structural and mechanistic characteristics of GemC/AraC. Employing Pol η to bypass GemC/AraC inhibited elongation during an in crystallo analysis bears implications for the development of more potent and efficient drugs for cancer patients. Incorporation results characterized both AraC and GemC with lower binding affinity compared to the native nucleoside, dCTP. Structurally, however, crystallization of Pol η with AraC/GemC at the insertion site revealed minimal change from dCTP. Further, we will crystallize Pol η with AraC/GemC at the primer terminus to investigate their inhibition mechanisms.

Poster Session Link: https://gather.town/invite?token=0pEoq7VP

If you have any questions for the presenter, please contact them via email: mora9135@pacificu.edu