Cellular toxicity of zidovudine (AZT) in DT40 and the role of MRE11 and polymerase ε nucleases in cellular tolerance to AZT treatment

Abstract

An antiretroviral therapy regime, based on nucleoside reverse transcriptase inhibitors (NRTIs), has revolutionised the treatment of acquired immunodeficiency syndrome (AIDS). Although NRTIs can successfully suppress viral replication, they are not without significant toxicity, which can seriously compromise treatment effectiveness. AZT, an example of NRTIs, integrates into the viral genome function as a chain terminator, which halts viral replication. The side effect of AZT is toxicity to mitochondrial or nuclear DNA. AZT also acts as a substrate for human mitochondrial DNA (mtDNA) polymerase γ, resulting in inhibition of its replication. The cellular mechanisms behind AZT toxicity are not well understood. The Hartsuiker lab reports that MRE11 and DNA Polε are involved in resistance to gemcitabine. We aimed to investigate a similar role of MRE11 and Polε in cellular tolerance to AZT. Our preliminary results suggest that Polεexo-/- , and nuclease dead mutant MRE11H129N/- cells display increased sensitivity to zidovudine compared to wild type and MRE+/- DT40 cells, respectively. These findings show that knowledge of DNA repair mechanisms can be utilised to encourage improvements in chemotherapy treatment and could play an essential role in precision medicine.