Synthesis of fluorinated analogs of oxidative DNA lesions and their use to probe features of recognition and repair by base excision repair glycosylases
Damage to DNA occurs through various sources, both exogenous and endogenous. Base lesions resulting from the oxidation of guanine include 8-oxo-7,8-dihydroguanine (OG), guanidinohydantoin (Gh), and spiroiminodihydantoin (Sp). These modified bases can form mismatches and lead to a G - C and G - T transversion mutations in DNA. Fortunately, these lesions are recognized and removed by DNA repair glycosylases found in all organisms. This work explores the features of recognition and repair of these oxidized guanine lesions by a diverse set of base excision glycosylases (MutY, Fpg, hOGG1, Nei, hNEIL1) using synthesized 2’ fluorinated nucleosides such as 2’-fluoro-adenosine (FA), 2’-fluoro-8-oxo-guanosine (FOG), 2’-fluoro-guanidinohydan-toin (FGh), and 2’-fluoro-spiroiminodihydantoin (FSp).