DNA-Protein cross-links: cellular effects and repair mechanisms

DNA-蛋白质交联：细胞效应和修复机制

• 批准号: 8759022
• 负责人: COLIN R CAMPBELL
• 金额: $ 38.71万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-21 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8759022
• 关键词: Affinity; Aging; Alkylating Agents; Antineoplastic Agents; Biological; Biological Assay; Brain; Bypass; Cancer Biology; Carcinogens; Cardiovascular Diseases; Cell Culture Techniques; Cell Death; Cells; Chemicals; Circular DNA; Conflict (Psychology); DNA; DNA Repair; DNA biosynthesis; DNA lesion; DNA repair protein; DNA-Directed DNA Polymerase; DNA-Protein Interaction; Data; Dependence; Development; Environmental Pollutants; Evaluation; Excision; Exposure to; Free Radicals; Genetic; Genetic Engineering; Genetic Recombination; Genetic Transcription; Genome; Goals; Guanine; Heart; Heart Diseases; Human; In Vitro; Ionizing radiation; Lead; Lesion; Lipid Peroxidation; Literature; Malignant Neoplasms; Mammalian Cell; Mass Spectrum Analysis; Mechlorethamine; Methodology; Molecular; Molecular and Cellular Biology; Mutagenesis; Mutation; Nature; Nucleotide Excision Repair; Occupational; Organic Synthesis; Outcome; Pathway interactions; Pharmaceutical Preparations; Plasmids; Platinum Compounds; Play; Positioning Attribute; Property; Protein Engineering; Proteins; Reactive Oxygen Species; Research; Role; Site; Structure; System; Testing; Time; Tissues; Toxic Environmental Substances; Toxic effect; Toxin; Transcription-Coupled Repair; Transition Elements; Ultraviolet Rays; Work; Xenobiotics; Yeasts; adduct; age related; age related neurodegeneration; anticancer activity; antitumor drug; base; chemotherapeutic agent; clinically relevant; coping; crosslink; cytotoxic; cytotoxicity; erythritol anhydride; genotoxicity; homologous recombination; human DNA; human disease; insight; irradiation; novel; public health relevance; recombinational repair; repaired; research study; synthetic construct

DESCRIPTION (provided by applicant): DNA-protein cross-links (DPCs) are super-bulky, helix-distorting DNA lesions that result from exposure to a variety of chemical and physical agents such as antitumor drugs, environmental/ occupational toxins, ionizing radiation, and endogenous free radical-generating systems. Due to their unusually bulky nature, DPCs are hypothesized to interfere with normal DNA-protein interactions required for DNA replication, transcription, and repair, potentially leading to mutagenesis, genotoxicity, and cytotoxicity. However, the biological outcomes of DPC lesions in cells are poorly understood because of their inherent structural complexity and the difficulty of generating DNA substrates containing structurally defined DPC for biological evaluation. Our long-term goal is to elucidate the role tha spontaneous and induced DPCs play in human disease and in the anticancer activity of common chemotherapeutic agents. The objectives of this application are to determine the biological consequences of DPC formation in human cells and to discover the mechanism(s) responsible for the removal of DPCs from DNA. Our studies will for the first time systematically examine the influence of DPCs on DNA repair and replication. Our central hypothesis is that, if not repaired, DPCs exert mutagenic and cytotoxic effects, significantly contributing to the biological effects of many known carcinogens and antitumor drugs. Collectively, these studies will provide significant new insights into the molecular and cellular biology of DPCs and are expected to fundamentally advance the fields of DNA repair, cancer biology, and molecular mechanisms of aging.

描述（由申请人提供）：DNA-蛋白质交联（DPC）是由于暴露于各种化学和物理试剂（如抗肿瘤药物、环境/职业毒素、电离辐射和内源性自由基生成系统）而导致的超大体积、螺旋扭曲DNA损伤。由于其异常庞大的性质，假设DPC干扰DNA复制、转录和修复所需的正常DNA-蛋白质相互作用，可能导致诱变、遗传毒性和细胞毒性。然而，细胞中DPC病变的生物学结果知之甚少，因为它们固有的结构复杂性和难以产生含有结构确定的DPC的DNA底物用于生物学评价。我们的长期目标是阐明自发性和诱导性DPC在人类疾病和常见化疗药物的抗癌活性中的作用。本申请的目的是确定DPC在人细胞中形成的生物学后果，并发现负责从DNA中去除DPC的机制。我们的研究将首次系统地研究DPC对DNA修复和复制的影响。我们的中心假设是，如果不修复，DPC发挥诱变和细胞毒性作用，显着促进许多已知的致癌物和抗肿瘤药物的生物学效应。总的来说，这些研究将为DPC的分子和细胞生物学提供重要的新见解，并有望从根本上推进DNA修复，癌症生物学和衰老分子机制等领域。