Damaged DNA Recognition as a Cancer Avoidance Mechanism

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。如果不修复，产生的 DNA 损伤可能会发生错误编码（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）。 DNA 损伤导致的突变事件和表观遗传扰动已在人类癌症中得到证实。许多实验室的大量工作已经确定了一系列 DNA 损伤以及识别和消除这些损伤的特定修复活动。现在人们普遍认识到，某些 DNA 修复途径存在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 修复的相对率有关。在正常情况下，估计每个细胞每天会形成 104 至 105 个损伤。虽然这代表了很大的损伤负荷，但问题要复杂得多，因为损伤分散在人类基因组的 109 个正常碱基中。该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来探索发现、识别、选择性去除和修复病变的机制。该提案的重点是通过碱基切除修复（BER）途径修复的单碱基损伤。提出了三个具体目标来研究（目标 1）含有病变的寡核苷酸区域的热和热力学不稳定性作为病变识别的机制，（目标 2）可用于选择性去除受损碱基的修饰碱基取代基的大小、电子感应特性和官能团，以及（目标 3）DNA 连接酶可利用的核酸构象和动态特性，以防止连接受损、不适当或错配的 DNA 链。基地。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引起疾病的损害的机制的理解，并为一些抗肿瘤药物的机制提供新的见解。

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.