Repair of Inflammation-induced DNA damage

修复炎症引起的 DNA 损伤

基本信息

批准号：
8711464
负责人：
Seongmin Lee
金额：
$ 18.52万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8711464
关键词：
Affect Alkylation Amination Base Excision Repairs Base Pairing Binding Binding Proteins Biological Process Cancer Etiology Chronic Cleaved cell Complex CpG dinucleotide Cytosine DNA DNA Damage DNA Methylation DNA Methyltransferase DNA Modification Methylases DNA Repair DNA Repair Enzymes DNA biosynthesis DNA lesion DNA-Directed DNA Polymerase Development Dinucleoside Phosphates Enzymes Epigenetic Process Etiology Excision Gene Mutation Genetic Transcription Goals Guanine Halog Halogens Human Hydrogen Bonding Inflammation Lesion Malignant Neoplasms Mediating Methylation Modification Mutagenesis Mutation Peroxidases Proteins Public Health Rattus Research Roentgen Rays Role Specificity Structure base carcinogenesis design expectation halogenation human DNA insight killings malignant breast neoplasm pathogen programs public health relevance repair enzyme repaired transversion mutation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（申请人提供）：慢性炎症与癌变密切相关。炎症诱发癌变的一种潜在机制涉及髓过氧化物酶产生的活性卤素物质引起的 DNA 损伤和突变，以杀死病原体。由反应性卤素物质形成的主要DNA损伤包括8-卤代鸟嘌呤(haloG)，例如8-氯鸟嘌呤和8-溴鸟嘌呤。 HaloG 是一种促突变损伤，可触发损伤对面的 G 错误掺入，促进 G 突变为 C。最近，在大鼠中观察到 haloG 切除活性，但尚未鉴定出负责这种活性的酶。我们的初步研究表明，人 8-氧代鸟嘌呤糖基化酶 hOGG1 能有效地将 haloG 从 DNA 上切割下来，表明 hOGG1 是 haloG 的修复酶。我们拟议研究的中心假设是 haloG 是一种促突变损伤，影响各种生物过程，并通过碱基切除 DNA 修复进行修复。我们所提议项目的长期目标是阐明鸟嘌呤 8 修饰对 DNA 修复、DNA 复制、转录、DNA 甲基化和肿瘤发生等生物过程的影响。这里的目的是阐明 haloG 修复和 haloG 诱导突变的机制，并评估 haloG 对表观遗传机制的影响。作为实现我们长期目标的下一步，我们设计了三个具体目标：1) 阐明 hOGG1 的 haloG 识别和修复机制； 2) 阐明haloG介导的诱变的结构基础； 3) 评估CpG二核苷酸中的haloG对表观遗传机制的影响。我们期望这些项目的成功执行将增进我们对炎症引起的 DNA 损伤和修复以及炎症引起的病变对表观遗传机制的影响的理解，为了解慢性炎症在癌症病因学中的作用提供重要见解。