Repair of Inflammation-induced DNA damage

修复炎症引起的 DNA 损伤

• 批准号: 8570916
• 负责人: Seongmin Lee
• 金额: $ 22.55万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8570916
• 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

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。炎症诱导癌变的一个潜在机制涉及由髓过氧化物酶产生的活性卤素引起的DNA损伤和突变，以杀死病原体。由反应性卤素物质形成的DNA损伤主要包括8-氯鸟嘌呤和8-溴鸟嘌呤等8-卤化鸟嘌呤。HaloG是一种促生病变，可触发病变对面G的错误结合，促进G向C突变。最近，在大鼠中观察到haloG切除活性，但尚未确定负责这种活性的酶。我们的初步研究表明，人类8-氧鸟嘌呤糖基化酶hOGG1可以有效地从DNA中切割haloG，表明hOGG1是haloG的修复酶。我们提出的研究的中心假设是haloG是一种影响各种生物过程的促生病变，并通过碱基切除DNA修复。我们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。本文的目的是阐明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。为了实现我们的长期目标，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)阐明卤素介导突变的结构基础；3)评价CpG二核苷酸中haloG对表观遗传机制的影响。我们的期望是，这些项目的成功实施将促进我们对炎症诱导的DNA损伤和修复以及炎症诱导病变对表观遗传机制的影响的理解，为慢性炎症在癌症病因学中的作用提供重要的见解。