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: 7344834
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7344834
• 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

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）：所有生物体的DNA都不断受到内源性和外源性物质的攻击。如果不进行修复，由此产生的DNA损伤可能会编码错误（诱变效应），或改变DNA-蛋白质相互作用的特异性（表观遗传效应）。突变事件和由DNA损伤引起的表观遗传扰动已经在人类癌症中被确定。许多实验室的大量工作已经确定了一系列DNA损伤以及识别和清除这些损伤的特定修复活动。现在人们普遍认识到，在某些DNA修复途径中有缺陷的个体容易患上特定形式的癌症。基因正常个体的癌症易感性可能与DNA损伤和DNA修复的相对比率有关。在正常情况下，估计每个细胞每天形成104到105个病变。虽然这代表了很大的病变负荷，但问题实际上更加复杂，因为病变分散在人类基因组的109个正常碱基中。本提案中描述的工作的总体目标是通过一组涉及混合量子力学和分子力学方法的相关实验和计算研究，探索病变被发现、识别、选择性移除和修复的机制。本建议的重点是通过碱基切除-修复（BER）途径修复单碱基病变。提出了三个具体目标来研究（目标1）含有损伤的寡核苷酸区域的热和热力学不稳定性作为损伤识别的机制；（目标2）可用于选择性去除损伤碱基的修饰基取代基的大小、电子感应性质和官能团；以及（目标3）核酸的构象和动态特性，这些特性可以被DNA连接酶利用，以防止DNA链与受损、不适当或错配的碱基连接。这里提出的研究结果将大大增加我们对保护人类基因组免受致病损伤的机制的理解，并为一些抗肿瘤药物的机制提供新的见解。