Chronic inflammation is closely associated with carcinogenesis. One potential mechanism for inflammation-induced carcinogenesis involves DNA damage and mutation caused by reactive halogen species that are produced by myeloperoxidase to kill pathogens. The major DNA lesions formed by reactive halogen species include 8-halogenated guanine (haloG) such as 8- chloroguanine and 8-bromoguanine. HaloG is a promutagenic lesion that can trigger misincorporation of G opposite the lesion, promoting G to C mutation. Recently, haloG excision activity was observed in rats, yet an enzyme responsible for such activity has not been identified. Our preliminary study showed that human 8-oxoguanine glycosylase hOGG1 efficiently cleaves haloG from DNA, suggesting hOGG1 as a repair enzyme for haloG. Our central hypothesis of the proposed research is that haloG is a promutagenic lesion that affects various biological processes, and repaired by base excision DNA repair. Our long-term goal of the proposed programs is to elucidate the effects of guanine 8-modification on biological processes such as DNA repair, DNA replication, transcription, DNA methylation, and tumorigenesis. The objectives here are to elucidate mechanisms of haloG repair and haloG- induced mutagenesis and to evaluate the effects of haloG on epigenetic mechanisms. As a next step for achieving our long-term goals, we have designed three Specific Aims that are 1) Elucidating haloG recognition and repair mechanisms of hOGG1;2) Clarifying structural basis for haloG-mediated mutagenesis;and 3) Evaluating the effects of haloG in CpG dinucleotides on epigenetic mechanisms. Our expectation is that the successful execution of these programs would advance our understanding on the inflammation-induced DNA damage and repair and the effects of inflammation-induced lesion on epigenetic mechanisms, providing important insights into the role of chronic inflammation in cancer etiology.

Public Health Relevance

The research proposed here is relevant to public health because it aims to elucidate the mechanisms underlying inflammation-induced DNA damage, repair, and mutagenesis. Since chronic inflammation is closely associated with development of cancer, accomplishing our goal will contribute to better understanding of the role of chronic inflammation-induced DNA damage in cancer etiology.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Exploratory/Developmental Grants (R21)
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Cancer Etiology Study Section (CE)
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Reinlib, Leslie J
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University of Texas Austin
Schools of Pharmacy
United States
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Kou, Yi; Koag, Myong-Chul; Lee, Seongmin (2015) N7 methylation alters hydrogen-bonding patterns of guanine in duplex DNA. J Am Chem Soc 137:14067-70
Koag, Myong-Chul; Kou, Yi; Ouzon-Shubeita, Hala et al. (2014) Transition-state destabilization reveals how human DNA polymerase ? proceeds across the chemically unstable lesion N7-methylguanine. Nucleic Acids Res 42:8755-66
Koag, Myong-Chul; Nam, Kwangho; Lee, Seongmin (2014) The spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase ?. Nucleic Acids Res 42:11233-45
Koag, Myong-Chul; Lee, Seongmin (2014) Metal-dependent conformational activation explains highly promutagenic replication across O6-methylguanine by human DNA polymerase ?. J Am Chem Soc 136:5709-21