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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES023101-02
Application #
8711464
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Reinlib, Leslie J
Project Start
2013-08-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
$185,150
Indirect Cost
$61,400
Name
University of Texas Austin
Department
None
Type
Schools of Pharmacy
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712