Cancer susceptibility of XRCC1 mutant mice

描述(申请人提供)：这项建议的主要焦点是研究DNA修复基因XRCC1的功能变异可以影响致癌物诱导的肿瘤发生的易感性这一概念。XRCC1已被证明在碱基切除修复、单链修复以及可能的双链修复中起关键作用。许多XRCC1基因的多态已经被发现，癌症相关性研究受到了广泛的流行病学关注，但结果相互矛盾。为了帮助验证DNA修复，特别是XRCC1在环境致癌中的重要生物学作用，我们建议使用代表人类单倍体不足和多态的突变小鼠模型。XRCC1没有已知的酶活性，但依赖于蛋白质之间的相互作用来实现其在DNA修复中的功能。因此，使用生物系统，如小鼠，来帮助确定与可观察到的肿瘤表型在致癌物作用下的表达相关的功能，是研究XRCC1功能的主要手段。偶氮甲烷(AOM)是一种烷化剂，也是一种公认的致癌物，在小鼠的结肠和肝脏有一系列肿瘤前、癌前和恶性病变，程度较轻。它也是环境中存在的可能存在重大暴露风险的烷基化试剂的原型。我们的假设是XRCC1单倍体不足和单核苷酸多态R194W和R280H可能影响癌症对AOM的易感性。我们建议的研究产生的信息可以用来帮助设计临床相关的研究，以确定在特定环境条件下可能面临更高癌症风险的个人或群体。公共卫生相关性：这项提案的主要焦点是调查DNA修复基因XRCC1的功能变异可以影响致癌物诱导肿瘤发生的易感性这一概念。XRCC1已被证明在碱基切除修复、单链修复以及可能的双链修复中起关键作用。许多XRCC1基因的多态已经被发现，癌症相关性研究受到了广泛的流行病学关注，但结果相互矛盾。为了帮助验证DNA修复，特别是XRCC1在环境致癌中的重要生物学作用，我们建议使用代表人类单倍体不足和多态的突变小鼠模型。

DESCRIPTION (provided by applicant): The main focus of this proposal is investigation of the concept that functional variation in the DNA repair gene XRCC1 can influence susceptibility to carcinogen-induced tumorigenesis. XRCC1 has been shown to be a key player involved in base excision repair, single strand break repair, and possibly double strand break repair. A number of XRCC1 polymorphisms have been identified, and cancer association studies have received extensive epidemiological attention but with conflicting results. In order to help validate the important biological role of DNA repair and specifically XRCC1, in environmental carcinogenesis we are proposing to use mutant mouse models representing human haploinsufficiency and polymorphisms. XRCC1 has no known enzymatic activity, but depends on protein to protein interactions to carry out its functional role in DNA repair. Therefore, use of a biological system such as the mouse to help define function related to expression of an observable tumor phenotype when challenged with a carcinogen is a major means of investigating XRCC1 function. Azoxymethane (AOM) is an alkylating agent and a well-established carcinogen in mice with a spectrum of pre-tumor, pre-malignant, and malignant lesions in the colon and to a lesser extent the liver. It also serves as a prototype for alkylating agents present in the environment that present potentially significant exposure risks. Our hypothesis is that cancer susceptibility to AOM can be influenced by XRCC1 haploinsufficiency and single nucleotide polymorphisms R194W and R280H. Information generated from our proposed studies could be used to help design clinically relevant studies to identify individuals or groups that may be at increased cancer risk for specific environmental conditions. PUBLIC HEALTH RELEVANCE: The main focus of this proposal is investigation of the concept that functional variation in the DNA repair gene XRCC1 can influence susceptibility to carcinogen-induced tumorigenesis. XRCC1 has been shown to be a key player involved in base excision repair, single strand break repair, and possibly double strand break repair. A number of XRCC1 polymorphisms have been identified, and cancer association studies have received extensive epidemiological attention but with conflicting results. In order to help validate the important biological role of DNA repair and specifically XRCC1, in environmental carcinogenesis we are proposing to use mutant mouse models representing human haploinsufficiency and polymorphisms.