8-oxoguanine (G*), arguably the most important mutagenic and carcinogenic DNA lesion, is induced by ionizing radiation (IR) and other environmental agents, or is formed endogenously due to oxidative stress (commonly used as the senitel marker for cellular oxidative damage). G* is mutagenic because of its mispairing with A during DNA synthesis. Repair of G* in DNA occurs via the base excision repair (BER) pathway, and is initiated with its removal by a G*-DNA glycosylase (OGG). The major human OGG (hOGG-1) was cloned in 1997. The lack of earlier evidence for OGG activity in human cells now appears to be due to a G*-specific binding protein (OGBP) whose physiological role is unknown, as is the relationship between the hOGG-1 and a recently identified mitochondrial OGG. The cloned hOGG-1 removes G* from an G* C, but not from an G* A pair, consistent with the rationale that the latter reaction will fix mutations when G* is formed in DNA. However, G* can also be incorporated into DNA from the nucleotide pool, requiring removal from the nascent strand to prevent mutation. A second OGG (OGG- 2), which removes G* from G* A pairs and is antigenically distinct from hOGG-1, has now been identified in both human cells and yeast. Our discovery of human OGG-2 has led us to propose a novel model for repair of G* in DNA. Our model predicts that OGG-2 is nascent-strand specific and utilizes the mismatch repair system. The primary objective of this project is to test the hypotheses derived from the model, and to elucidate the possible role of OGBP in the antimutagenic processing of G*.
The specific aims of this project are: (1) To clone hOGG-2 and produce recombinant OGG polypeptides for collaborative structural studies; (2) to test the hypothesis that hOGG-2 interacts with mismatch repair and DNA replication complexes; (3) to compare the structural bases for the substrate range and substrate discrimination of hOGG-1 and hOGG-2; (4) to purify and characterize OGBP in order to elucidate its biological role; and (5) to investigate the relationship between the mitochondrial and nuclear OGGs.
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