Oxidative stress leads to increased mutagenesis and reduced genomic stability. This arises in part from guanine oxidation in DNA or nucleotide pools, with the most common being 8-oxoG or 8-oxodGTP. This modification results in the dual coding potential where (anti) 8-oxoG base pairs with cytosine (Cy) and (syn) 8-oxoG base pairs with adenine (Ad). During subsequent rounds of replication the (syn) 8-oxoG:Ad base pair can result in a C:G to A:T transversion. DNA polymerases bypass 8-oxoG or insert 8-oxodGTP in a mutagenic manner, and the molecular mechanism by which this oxidative DNA damage is processed by DNA polymerases remains under investigation. To probe the mechanism of nucleotide insertion, crystallography was used with a model DNA polymerase to capture key events explaining 8-oxodG accommodations in the active site. Combining this approach with solution and quantum mechanical analyses revealed new insights into the strategies polymerases use to handle oxidative DNA damage.

DNA polymerase dynamics involving the mutagenic and non-mutagenic 8-oxoG lesion

248th National Meeting (2014)

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