Assessment of functional overlaps between human DNA repair pathways for 8-oxoguanine

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Generation of reactive oxidative species (ROS) and the resulting damage to DNA are unavoidable under physiological conditions and can be amplified by exogenous stressors, such as radiation, drugs and chemical compounds from diet and environmental sources. With an estimated generation rate of >1000 per day, 8-oxo-7,8-dihydroguanine (8-oxoG) is the most frequent oxidative DNA lesion in mammalian cells. 8-OxoG is pre-mutagenic due to the non-canonical (Hoogsteen type) base pairing with adenine during DNA replication. The resulting 8-oxoG:A mispairs, if persist into the next round of replication, produce characteristic G:C to T:A transversion mutations. A comprehensive defense pathway termed “GO system” protects from mutation by both eliminating 8-oxo-dGTP from the nucleotide pool and removing the 8-oxoG:C and 8-oxoG:A lesions from the genome. Base excision repair (BER) is the primary mechanism for repair of these DNA lesions in human cells; however, several lines of evidence suggested existence of auxiliary mechanisms in addition to the canonical BER. The proposed project is focused at identification of functional overlaps between BER and other DNA repair pathways in safeguarding human cells against the effects of 8-oxoG. We will address the existence of alternative mechanisms potentially relevant to the repair of 8-oxoG at three different levels: removal of pre-mutagenic 8-oxoG, prevention of toxicity at the post-excision step, and correction of the ultimately mutagenic 8-oxoG:A mispairs.