Cancer susceptibility of XRCC1 mutant mice

描述（由申请人提供）：本提案的主要重点是研究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。XRCC1已被证明是参与碱基切除修复、单链断裂修复和可能的双链断裂修复的关键参与者。许多XRCC1多态性已被确定，癌症相关性研究已受到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不足和多态性的突变小鼠模型。XRCC1没有已知的酶活性，但依赖于蛋白质与蛋白质的相互作用来实现其在DNA修复中的功能作用。因此，研究XRCC1功能的主要手段是利用生物系统（如小鼠）来帮助确定与可观察到的肿瘤表型表达相关的功能，当受到致癌物的攻击时。偶氮氧甲烷（AOM）是一种烷基化剂，是一种公认的致癌物，在结肠和较小程度的肝脏中具有肿瘤前、恶性前和恶性病变的小鼠中存在。它还可以作为环境中存在的烷基化剂的原型，这些烷基化剂存在潜在的重大暴露风险。我们的假设是，癌症对AOM的易感性可能受到XRCC1单倍不全和R194W和R280H单核苷酸多态性的影响。从我们提出的研究中产生的信息可用于帮助设计临床相关研究，以确定特定环境条件下可能增加癌症风险的个人或群体。公共卫生相关性：本提案的主要重点是研究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。XRCC1已被证明是参与碱基切除修复、单链断裂修复和可能的双链断裂修复的关键参与者。许多XRCC1多态性已被确定，癌症相关性研究已受到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不足和多态性的突变小鼠模型。

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.