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（由申请人提供）：慢性炎症与癌变密切相关。炎症诱导的致癌作用的一种潜在机制涉及由脊髓过氧化物酶产生的反应性卤素物质引起的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病变包括8-卤代的鸟嘌呤（卤素），例如8-氯瓜氨酸和8-溴瓜氨酸。 Halog是一种正当的病变，可以引发与病变相对的G的错误结构，从而促进G至C突变。最近，在大鼠中观察到卤素切除活性，但是尚未鉴定出负责这种活性的酶。我们的初步研究表明，人8-氧气糖基糖基酶HogG1有效地从DNA裂解了卤素，这表明HOGG1是卤素的修复酶。我们对拟议的研究的中心假设是，卤素是影响各种生物学过程的正当病变，并通过碱基切除DNA修复进行修复。我们提出的计划的长期目标是阐明鸟嘌呤8-修饰对DNA修复，DNA复制，转录，DNA甲基化和肿瘤发生的影响。这里的目标是阐明卤素修复和卤素诱导的诱变的机制，并评估卤素对表观遗传机理的影响。作为实现长期目标的下一步，我们设计了三个特定目标，即1）阐明HOGG1的卤素识别和修复机制； 2）阐明卤素介导的诱变的结构基础； 3）评估卤素对CpG二核苷酸对表观遗传机制的影响。我们的期望是，这些程序的成功执行将提高我们对炎症引起的DNA损伤和修复的理解，以及炎症引起的病变对表观遗传机制的影响，从而为慢性炎症在癌症病因中的作用提供了重要的见解。