Structure and Function of DNA Repair Enzymes and Cancer

DNA 修复酶的结构和功能与癌症

基本信息

批准号：
10014581
负责人：
Sylvie Doublie
金额：
$ 183.72万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-03 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10014581
关键词：
Affect Base Excision Repairs Basic Science Biochemical Biochemistry Bioinformatics Biological Cancer Biology Cancer Etiology Cell Culture Techniques Cells Cellular biology Chromatin Chromatin Structure DNA Damage DNA Repair DNA Repair Enzymes DNA analysis DNA glycosylase Data Defect Enzymes Failure Family Genes Genetic Variation Genomic Instability Germ-Line Mutation Goals Human Human Cloning Human Genetics Individual Knowledge Lead Malignant Neoplasms Mutation Pathway interactions Predisposition Process Proteins Resistance Resource Sharing Risk Assessment Structure Testing Translating Treatment Efficacy Variant Work cancer prevention cancer therapy carcinogenesis gene repair insight molecular imaging multidisciplinary mutant personalized medicine predictive marker programs repair enzyme repaired response single molecule structural biology targeted treatment tumor tumor progression

Affect Base Excision Repairs Basic Science Biochemical Biochemistry Bioinformatics Biological Cancer Biology Cancer Etiology Cell Culture Techniques Cells Cellular biology Chromatin Chromatin Structure DNA Damage DNA Repair DNA Repair Enzymes DNA analysis DNA glycosylase Data Defect Enzymes Failure Family Genes Genetic Variation Genomic Instability Germ-Line Mutation Goals Human Human Cloning Human Genetics Individual Knowledge Lead Malignant Neoplasms Mutation Pathway interactions Predisposition Process Proteins Resistance Resource Sharing Risk Assessment Structure Testing Translating Treatment Efficacy Variant Work cancer prevention cancer therapy carcinogenesis gene repair insight molecular imaging multidisciplinary mutant personalized medicine predictive marker programs repair enzyme repaired response single molecule structural biology targeted treatment tumor tumor progression

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项目摘要

PROJECT SUMMARY On a daily basis, each cell in our body is bombarded with some 30,000 endogenous DNA damages per day, the vast majority of which are repaired by Base Excision Repair (BER). The central hypothesis of this Program is that, understandably, defects in this BER process drive human carcinogenesis and affect responses to cancer treatments. The overall goal of this Program Project is to functionally characterize human genetic variation in the BER enzymes. To accomplish this, we are characterizing potentially damaging germline and tumor-associated SNPs in the B E R DNA glycosylases, and a number of the downstream enzymes in the BER pathway, using our strengths in bioinformatics, cell biology, biochemistry, structural biology and single molecule imaging in order to determine the functions of the wild-type and variant proteins. Our preliminary data suggest that fundamental mechanistic studies are essential for interpreting human genetic variation and its influence on cancer etiology and tumor progression. Our program is informed and driven by the identification and characterization of germline and tumor-associated enzyme variants that may contribute to the altered DNA repair capacity of human BER enzymes. To realize our goals, variants in the BER genes are prioritized for study using bioinformatics (Core A) as well as enzymatic activity and structural information (Project 2). We then test for functional consequences of the variation using a powerful combination of biological, biochemical, structural, and single-molecule approaches. Core A provides the bioinformatics underpinning of the Program; Project 1, the biological studies of the human variant proteins in human cells; Project 2, the structure/function and biochemical analyses of the BER glycosylases; Project 3, the study of the BER repair process in chromatin; and Project 4, insights into the damage target search of the wild-type and variant BER proteins. Core B provides purified proteins to Projects 2-4 and cell cultures of variant clones to Projects 1-4, while Core C provides the administrative support. Taken together, the mechanistic results obtained by this Program Project provide a unique opportunity to underpin critical questions surrounding cancer etiology and cancer treatment, thus substantially impacting personalized medicine.

项目摘要每天，我们体内的每个细胞每天都会被约30,000个内源性DNA损伤轰炸，其中绝大多数是通过基础切除修复（BER）修复的。该计划的中心假设可以理解的是，在此BER过程中的缺陷驱动了人类的致癌作用并影响对癌症治疗。该计划项目的总体目标是在功能上表征人类遗传 BER酶的变化。为此，我们正在表征潜在的破坏种系，并且 B e R DNA糖基化酶中与肿瘤相关的SNP，以及许多下游酶 BER途径，利用我们在生物信息学，细胞生物学，生物化学，结构生物学和单一方面的优势分子成像以确定野生型和变体蛋白的功能。我们的初步数据表明，基本机械研究对于解释人类至关重要遗传变异及其对癌症病因和肿瘤进展的影响。我们的计划已通知，受生殖线和与肿瘤相关的酶变体的鉴定和表征的驱动可能导致人类BER酶的DNA修复能力改变。为了实现我们的目标，变种使用生物信息学（核心A）以及酶活性和结构信息（项目2）。然后，我们使用功能强大的生物学，生化，结构和单分子方法的结合。核心A提供该计划的基础的生物信息学；项目1，人类变异蛋白的生物学研究人类细胞；项目2，BER糖基酶的结构/功能和生化分析；项目3，染色质中BER修复过程的研究；和项目4，对损害目标搜索的见解野生型和变体BER蛋白。核心B为项目2-4和细胞提供纯化的蛋白质项目1-4的变体克隆文化，而核心C提供了行政支持。在一起，该计划项目获得的机械结果提供了一个独特的机会来支撑关键围绕癌症病因和癌症治疗的问题，从而实质上影响了个性化药品。