Computational investigation of oxidative damage to guanine: formation, recognition and removal by DNA repair enzymes in humans and bacteria

Abstract

Formation of guanine oxidation products is among the most frequently occurring DNA damaging events, and has been suspected to be related to aging, Alzheimer’s disease and various types of cancer. Guanine oxidative products are removed and replaced through the base excision repair (BER) pathway, which involves several enzymes including DNA glycosylases. BER is initiated when a DNA glycosylase detects a lesion and removes the damaged nucleobase. The present thesis employs computational chemistry to investigate the formation mechanisms of two guanine oxidation products, namely 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) and 7,8-dihydro-8-oxoguanine (OG). Moreover, several steps during the repair processes catalyzed by human (hOgg1) and bacterial (FPG) DNA glycosylases, including the lesion recognition, base removal, DNA backbone cleavage, and hydrolysis of the resulting DNA‒enzyme complex, are investigated using quantum mechanical and molecular dynamics approaches. The atomic-level details provided by these calculations show the differences in the recognition and removal mechanisms catalyzed by human and bacterial glycosylases.