XPC Haplotypes Alter DNA Repair Capacity and Levels of Genetic Damage

着色性干皮病互补组C （XPC）是全基因组核苷酸切除修复中DNA损伤的关键识别因子。XPC功能的完全丧失导致一种称为色素性干皮病的疾病。尽管XP代表了XPC蛋白功能的极端缺陷，但由于与某些遗传性癌症易感性有关的单核苷酸多态性（snp）的遗传，该蛋白的功能在一般人群中会发生细微的变化。迄今为止，已经报道了超过90个XPC基因的snp，分析这些snp对疾病风险的影响或评估个体表型效应是不切实际的。然而，众所周知，人类群体中的遗传变异不是以独立的snp排列，而是以各种snp（单倍型）的组合排列。因此，应该检查单倍型的表型效应，而不是单核苷酸多态性，以确定遗传变异在疾病风险中的作用。据我们所知，既没有对整个XPC基因组序列进行全面的单倍型分析，也没有对XPC单倍型的功能效应进行评估。我计划通过测试我的基因型/表型假设来解决这些知识上的空白，特别是某些XPC单倍型对转录过程和/或蛋白质完整性产生不利影响，从而表现出DNA修复能力的损伤，从而导致更高水平的持续遗传损伤。我使用生物信息学对XPC的整个基因组序列进行了全面的单倍型分析，并在吸烟者群体中描述了单倍型对遗传损伤的影响，我将其作为环境暴露人群的模型。为了验证这一假设，提出了以下具体目标：目标1：确定XPC单倍型对DNA修复能力（DRC）和遗传损伤的生物学效应（特别是基因型/表型关系）。目的2：通过定义XPC单倍型对转录和蛋白表达的影响来表征XPC单倍型的功能意义。

Xeroderma pigmentosum complementation group C (XPC) is the key recognition factor of DNA damage in global genome nucleotide excision repair. Complete loss of XPC function results in a disease known as Xeroderma pigmentosum. Although XP represents an extreme defect in the function of the XPC protein, subtle variation in the function of this protein occurs in the general population due to inheritance of single nucleotide polymorphisms (SNPs) which are implicated in some inherited cancer susceptibilities. To date, over 90 SNPs in the XPC gene have been reported an analysis of the effect of these on disease risk, or evaluation of individual phenotypic effects, is impractical. However, it is known that genetic variation in human populations is not arrayed as independent SNPs but as various combinations of SNPs (haplotypes). Therefore, the phenotypic effects of haplotypes, rather than SNPs, should be examined to determine the role of genetic variability in disease risk. To our knowledge, neither a comprehensive haplotype analysis of the entire XPC genomic sequence nor an evaluation of the functional effects of the XPC haplotypes has been conducted. I plan to address these gaps in knowledge by testing my genotype/phenotype hypothesis, specifically that certain XPC haplotypes adversely modify transcriptional processes and/or protein integrity, and consequently exhibit impairments in DNA repair capacity which causes higher levels of persisting genetic damage. I used bioinformatics to and conducted a comprehensive haplotype analysis of the entire genomic sequence of XPC and characterize the effect of haplotypes on genetic damage in a population of smokers that I used as a model of an environmentally exposed population. To test this hypothesis the following Specific Aims are proposed: Aim 1: To determine biological effects of XPC haplotypes on DNA repair capacity (DRC) and genetic damage (specifically, genotype/phenotype relationships). Aim 2: To characterize functional significance of XPC haplotypes by defining effects of XPC haplotypes on transcription and protein expression.