Formation of abasic (AP) sites-derived covalent DNA adducts and their role in inhibition of base excision repair (BER) pathway
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Apurinic/apyrimidinic (AP, also known as abasic) sites are ubiquitous in both cellular and synthetic DNA. The aldehyde form of an AP site provides a highly reactive moiety that plays a critical role in various biochemical processes. Over the last decade, Gates' group has extensively studied the reactivity of AP sites in both endogenous and exogenous contexts. In this dissertation, I investigate the interactions between AP sites and two small molecules, hydralazine and ethidium bromide, to explore their potential for covalent bonding with AP sites and the implications for DNA repair pathways. Hydralazine was found to rapidly form reversible hydrazone-derived adducts, which undergo oxidative cyclization to yield a stable triazolo[3,4-a]phthalazine adduct with AP sites in duplex DNA. The hydralazine-AP adducts completely block the activity of the central base excision repair enzyme, AP endonuclease 1 (APE1), in duplex DNA. This inhibition sensitizes SF295 glioblastoma cancer cells to the cytotoxic effects of the chemotherapeutic agent temozolomide (TMZ). These findings suggest that hydralazine could be repurposed to enhance the efficacy of DNA-damaging chemotherapies by targeting the BER pathway. In addition to hydralazine, I also characterized a novel covalent adduct between ethidium bromide and AP sites in both single-stranded and duplex DNA. The formation of ethidium-AP adducts underlines a previously unreported covalent binding mechanism, which could have significant implications for molecular biology techniques and our understanding of DNA damage response
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Ph. D.