Damaged DNA Recognition as a Cancer Avoidance Mechanism

受损 DNA 识别作为一种癌症预防机制

• 批准号: 7172331
• 负责人: Lawrence C Sowers
• 金额: $ 24.1万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7172331
• 关键词: Antiviral Agents; Base Excision Repairs; Base Pairing; Base Sequence; Biochemical; Cells; Chemical Structure; Complex; Computing Methodologies; Condition; Cytosine; DNA; DNA Damage; DNA Ligases; DNA Ligation; DNA Repair Pathway; DNA lesion; DNA-Protein Interaction; Deamination; Defect; Development; Discrimination; Disease; Electronics; Enzymes; Epigenetic Process; Event; Excision; Future; Genome; Goals; Helix (Snails); Human; Human Genome; Hybrids; Hydrolysis; Individual; Kinetics; Laboratories; Lesion; Ligase; Link; Literature; Malignant Neoplasms; Measurement; Measures; Mechanics; Methods; Modeling; Modification; Molecular; Molecular Conformation; Nucleic Acids; Nucleosides; Oligonucleotides; Organism; Pathway interactions; Pliability; Positioning Attribute; Predisposition; Process; Property; Pyrimidine; Pyrimidines; Range; Rate; Relative (related person); Reporting; Role; S Phase; Series; Site; Solid; Specificity; Structure; Thermodynamics; Thymine; Uracil; Vertebral column; Work; analog; antitumor agent; base; computer studies; day; ear helix; functional group; insight; member; nucleoside analog; oxidation; phosphodiester; prevent; quantum; repaired; research study; size; sugar; Antiviral Agents; Base Excision Repairs; Base Pairing; Base Sequence; Biochemical; Cells; Chemical Structure; Complex; Computing Methodologies; Condition; Cytosine; DNA; DNA Damage; DNA Ligases; DNA Ligation; DNA Repair Pathway; DNA lesion; DNA-Protein Interaction; Deamination; Defect; Development; Discrimination; Disease; Electronics; Enzymes; Epigenetic Process; Event; Excision; Future; Genome; Goals; Helix (Snails); Human; Human Genome; Hybrids; Hydrolysis; Individual; Kinetics; Laboratories; Lesion; Ligase; Link; Literature; Malignant Neoplasms; Measurement; Measures; Mechanics; Methods; Modeling; Modification; Molecular; Molecular Conformation; Nucleic Acids; Nucleosides; Oligonucleotides; Organism; Pathway interactions; Pliability; Positioning Attribute; Predisposition; Process; Property; Pyrimidine; Pyrimidines; Range; Rate; Relative (related person); Reporting; Role; S Phase; Series; Site; Solid; Specificity; Structure; Thermodynamics; Thymine; Uracil; Vertebral column; Work; analog; antitumor agent; base; computer studies; day; ear helix; functional group; insight; member; nucleoside analog; oxidation; phosphodiester; prevent; quantum; repaired; research study; size; sugar

DESCRIPTION (provided by applicant): The DNA of all organisms is constantly under attack by both endogenous and exogenous agents. If unrepaired, the resulting DNA lesions can miscode (mutagenic effects), or alter the specificity of DNA-protein interactions (epigenetic effects). Both mutational events and epigenetic perturbations resulting from DNA damage have been identified in human cancer. Substantial work from many laboratories has identified an array of DNA lesions as well as specific repair activities that recognize and remove these lesions. It is now widely recognized that individuals with defects in certain DNA repair pathways are predisposed to develop specific forms of cancer. Cancer susceptibility in genetically normal individuals is likely related to the relative rates of DNA damage and DNA repair. Under normal conditions, it is estimated that between 104 and 105 lesions are formed per cell per day. While this represents a large lesion load, the problem is substantially more complicated because the lesions are dispersed among the 109 normal bases in the human genome. The overall goal of the work described in this proposal is to probe the mechanisms by which lesions are found, identified, selectively removed and repaired through a group of linked experimental and computational studies involving hybrid quantum mechanical and molecular mechanical methods. The focus of this proposal is on single-base lesions repaired by the base excision-repair (BER) pathway. Three specific aims are proposed to investigate (aim 1) the thermal and thermodynamic instability of oligonucleotide regions containing lesions as a mechanism of lesion identification, (aim 2) size, electronic-inductive properties and functional groups of substituents of modified bases that can be exploited for the selective removal of damaged bases, and (aim 3) conformational and dynamic properties of nucleic acids that can be exploited by DNA ligase to prevent the ligation of DNA strands with damaged, inappropriate or mispaired bases. The results of the studies proposed here will substantially increase our understanding of mechanisms that protect the human genome from disease-causing damage and provide new insights into the mechanisms of some antitumor agents.

描述（由申请人提供）：所有生物的DNA不断受到内源和外源性剂的攻击。如果未修复，所得的DNA病变可能会错过（诱变作用），或改变DNA-蛋白质相互作用的特异性（表观遗传效应）。在人类癌症中已经确定了由DNA损伤引起的突变事件和表观遗传扰动。许多实验室的大量工作已经确定了一系列DNA病变以及识别和清除这些病变的特定维修活动。现在，人们广泛认识到，在某些DNA修复途径中缺陷的个体倾向于发展特定的癌症形式。遗传正常个体的癌症敏感性可能与DNA损伤和DNA修复的相对率有关。在正常条件下，据估计，每个细胞每天形成104至105个病变。尽管这代表了较大的病变负荷，但问题要复杂得多，因为病变分散在人类基因组中的109个正常碱基中。该提案中描述的工作的总体目标是探测通过一组涉及混合量子机械和分子机械方法的连接的实验和计算研究，通过一组连接的实验和计算研究发现，选择性地去除和修复病变的机制。该提案的重点是基础切除修复（BER）途径修复的单基碱病变。提出了三个特定的目的来研究（目标1）含有病变的寡核苷酸区域的热和热力学不稳定，作为病变鉴定的机制（目标2）大小，尺寸），电子电感特性和功能组的替代基碱的功能组，可用于选择性构酸的构成和（AIM 3）的特性，并将其构成（AIL 3）构成（目标3）。由DNA连接酶开发，以防止DNA链的连接，其损坏，不适当或误导的碱基。这里提出的研究结果将大大提高我们对保护人类基因组免受致病损害的机制的理解，并为某些抗肿瘤药物的机制提供新的见解。