Repair of 8-oxoG by hOGG1
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Repair of 8-oxoG by hOGG1

The genome of all living organisms are constantly exposed to exogenous and endogenous DNA-damaging agents and the greatest amount of damage is inflicted by the endogenous agents water and oxygen, which modify primarily the aromatic DNA bases. While ROS (Reactive Oxygen Species) such as hydroxyl radicals convert guanine (G) to 8-oxoguanine and thymine (T) to thymine glycol, water brings about the deamination of all bases carrying exocyclic amino groups (Ref.1).

Among the most deleterious of ROS-induced adducts is oxoG (7,8-dihydro-8-oxoguanine), which is formed by the oxidation of the guanine base in DNA. Guanine bases have a strong preference to pair with cytosine (C), but oxoG can pair both in Watson-Crick mode with cytosine and in Hoogsteen mode with adenine (A). In the Hoogsteen pairing mode, oxoG residues in DNA frequently mispair with adenine during replication, ultimately giving rise to G:C->T:A transversion mutations. These transversions are the second most common somatic mutation found in human cancers and are especially prevalent in the mutational spectrum of the tumor suppressor gene p53. Hence, oxoG has been implicated as a major endogenous mutagen that contributes broadly to spontaneous cell transformation (Ref.2).

hOGG1 (8-Oxoguanine-DNA Glycosylase) excise the oxoG base, leaving behind an abasic site that is restored to guanine by the cellular abasic site repair machinery. If the oxoG strand is replicated instead, the lesion preferentially mispairs with adenine to give an oxoG:A intermediate. Replication of the A strand in the oxoG:A intermediate completes the mutational process, resulting in an overall G:C->T:A transversion mutation. There are two pathways to repair 8-oxoG residues. One pathway involves cleavage of the AP site (apurinic or apyrimidinic) by APE1 (AP-Endonuclease-1), removal of the 5-dRP (deoxyribose phosphate) residue by dRP lyase activity of the Pol-Beta and incorporation of one nucleotide by the same polymerase. The second pathway involves the generation of a single nucleotide gap by the combined action of the AP lyase activity of DNA glycosylase and AP endonuclease. DNA Polymerase fills the gap and finally DNA Ligase seal the DNA ends broken during repair (Ref.3).

Oxidatively damaged bases in the genome are responsible for mutations leading to sporadic carcinogenesis. In particular 8-oxoG, and the AP site are among the most frequent mutagenic lesions formed in the human genome under physiological conditions (Ref.4).