Reactive oxygen species from endogenous and environmental sources induce oxidative damage to
DNA, and hence pose an enormous threat to the genetic integrity of cells. Such oxidative DNA damage is restored by the base excision repair (BER) pathway that is conserved from bacteria to humans and is initiated by
DNA glycosylases, which simply remove the aberrant base from the
DNA backbone by hydrolyzing the N-glycosidic bond (monofunctional
DNA glycosylase), or further catalyze the incision of a resulting abasic site (bifunctional
DNA glycosylase). In human cells, oxidative
pyrimidine lesions are generally removed by hNTH1, hNEIL1, or hNEIL2, whereas oxidative
purine lesions are removed by hOGG1. hSMUG1 excises a subset of oxidative base damage that is poorly recognized by the above
enzymes. Unlike these
enzymes, hMYH removes intact A misincorporated opposite template
8-oxoguanine during DNA replication. Although hNTH1, hOGG1, and hMYH account for major cellular glycosylase activity for inherent substrate lesions, mouse models deficient in the
enzymes exhibit no overt phenotypes such as the development of
cancer, implying backup mechanisms. Contrary to the mouse model, hMYH mutations have been shown to lead to a multiple colorectal
adenoma syndrome and high
colorectal cancer risk. For cleavage of the N-glycosidic bond, bifunctional
DNA glycosylases (hNTH1, hNEIL1, hNEIL2, and hOGG1) use Lys or Pro for direct attack on
sugar C1', whereas monofunctional
DNA glycosylases (hSMUG1 and hMYH) use an activated water molecule.
DNA glycosylases for oxidative damage, if not all, are covalently trapped by
DNA containing
2-deoxyribonolactone or
oxanine. Thus, the depletion of functional
DNA glycosylases using covalent trapping may reduce the BER capacity of
cancer cells, hence potentiating the efficacy of anticancer drugs or
radiation therapy.