XPC Haplotypes Alter DNA Repair Capacity and Levels of Genetic Damage

XPC 单倍型改变 DNA 修复能力和遗传损伤水平

• 批准号: 7914956
• 负责人: Catherine Michelle Rondelli
• 金额: $ 2.84万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2013-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914956
• 关键词: Address; Bioinformatics; Biological; DNA Damage; DNA Repair; DNA Repair Gene; Defect; Disease; Evaluation; Exhibits; Fellowship; Future; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Genome; Genomics; Genotype; Haplotypes; Human; Impairment; Individual; Inherited; Knowledge; Link; Malignant Neoplasms; Modeling; Molecular Biology; Nucleotide Excision Repair; Phenotype; Population; Predisposition; Process; Proteins; Public Health; Reporting; Role; Single Nucleotide Polymorphism; Smoker; Testing; Toxicology; Variant; Xeroderma Pigmentosum; citrate carrier; disorder risk; genetic variant; insight; interdisciplinary approach; protein expression; protein function; public health relevance; response

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This study will comprehensively examine the biological significance and the functional impact of genetic variants, in the context of haplotypes, of a key DNA repair gene. The multidisciplinary approach of this fellowship project will combine bioinformatics, molecular biology, and toxicology in order to obtain new mechanistic information on how adverse XPC haplotypes influence susceptibility genetic damage by environmental insult is linked to disease, as the biological effects of these haplotypes on DNA damage response and DNA repair capacity have not been previously evaluated. An obvious future direction is to transfer this genomic insight into public health precautions.

描述(申请人提供)：着色性干皮病C组(XPC)是全球基因组核苷酸切除修复中DNA损伤的关键识别因子。XPC功能的完全丧失会导致一种称为着色性干皮病的疾病。虽然XP代表了XPC蛋白功能的极端缺陷，但由于单核苷酸多态(SNPs)的遗传，该蛋白的功能在普通人群中发生了细微的变化，单核苷酸多态与一些遗传性癌症易感性有关。到目前为止，已经报道了XPC基因中超过90个SNP，分析这些SNP对疾病风险的影响，或评估个体表型影响是不切实际的。然而，众所周知，人类群体中的遗传变异并不是作为独立的SNPs排列的，而是作为SNPs(单倍型)的各种组合来排列的。因此，应该检查单倍型的表型效应，而不是SNPs，以确定遗传变异性在疾病风险中的作用。据我们所知，还没有对整个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/表型假说来解决这些知识差距，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，从而显示出DNA修复能力受损，从而导致更高水平的持续性遗传损伤。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，并表征了单倍型对吸烟者群体遗传损伤的影响，我将其用作环境暴露人群的模型。为了验证这一假说，提出了以下具体目标：目的1：确定XPC单倍型对DNA修复能力(DRC)和遗传损伤(特别是基因/表型关系)的生物学效应。目的：通过研究XPC单倍型对转录和蛋白表达的影响，探讨XPC单倍型的功能意义。 公共卫生相关性：这项研究将在单倍型的背景下，全面检查一个关键的DNA修复基因的遗传变异的生物学意义和功能影响。该奖学金项目的多学科方法将结合生物信息学、分子生物学和毒理学，以获得关于不利的XPC单倍型如何影响易感性的新的机制信息环境侮辱导致的遗传损伤与疾病有关，因为这些单倍型对DNA损伤反应和DNA修复能力的生物学效应以前还没有评估过。一个明显的未来方向是将这种基因组洞察力转化为公共卫生预防措施。