Single Nucleotide Resolution Map of Formation and Repair of Bulky Adducts in the Human Genome

人类基因组中大体积加合物的形成和修复的单核苷酸解析图

基本信息

批准号：
9186286
负责人：
AZIZ SANCAR
金额：
$ 46.84万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9186286
关键词：
Address Affect Antineoplastic Agents Area Basic Science Benzo(a)pyrene Blood Cells Carcinogens Cell Cycle Cell Cycle Stage Cell Differentiation process Cell Proliferation Cells Chemotherapy-Oncologic Procedure Chromatin Cisplatin DNA DNA Adduction DNA Adducts DNA Damage DNA Modification Process DNA Repair Enzymes DNA Sequence DNA lesion Data Development Diagnosis Disease susceptibility Environmental Carcinogens Event Excision Excision Repair Genome Genomic DNA Genomics Goals Human Human Genome Individual Differences Knowledge Lead Lesion Link Location Malignant Neoplasms Maps Methodology Methods Mission Mutagenesis Nucleotide Excision Repair Nucleotides Outcome Patients Physiological Platinum Positioning Attribute Predisposition Prevention strategy Public Health Qualifying Regulatory Pathway Repair Enzymology Research Resolution Risk Site Surgical incisions System Technology Therapeutic Effect UV induced Ultraviolet Rays United States National Institutes of Health Work Xenograft procedure adduct base cancer prevention cancer risk cancer therapy carcinogenesis cell type chemotherapeutic agent chemotherapy environmental carcinogenesis functional status genome-wide genome-wide analysis histone modification human disease improved innovation novel novel strategies programs repair enzyme repaired response stem cell differentiation tool whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Numerous environmental carcinogens and anti-cancer drugs form bulky base adducts in genomic DNA. However, the precise location of these lesions throughout the human genome is not known, and the factors that affect both damage formation and repair are difficult to study with currently available methodologies. Because the genomic location of damage and repair strongly influence the occurrence of pathological conditions, there is a need for new approaches for mapping damage and repair events across the entire genome. The long-term goal of our research program is to better understand how the nucleotide excision repair system targets the removal of bulky base adducts from DNA. The objective of this particular proposal is to further develop and apply novel tools for mapping carcinogen- and chemotherapy-induced DNA damage formation and repair throughout the genome and to identify the key factors that influence both the induction of DNA damage and the efficiency of damage removal by nucleotide excision repair. Our group’s background and expertise in the areas of DNA repair enzymology and genomics makes us uniquely qualified to address this issue. For this proposal, we will focus on identifying the precise locations of DNA base damage formed by the environmental carcinogens ultraviolet (UV) light and benzo[a]pyrene and by platinum-based cancer chemotherapies. We recently developed unique sequencing technologies that we have termed Damage-seq and XR-seq to provide high-resolution DNA sequence information on the formation and repair, respectively, of damage throughout the entire human genome. The rationale for the proposed research is that the ability to map damage and repair may reveal unexpected links between environmental carcinogens, mutagenesis, and human disease at specific genomic sites and suggest new strategies for diagnosing and treating human cancers. Our basic research on DNA adducts in cancer risk and prevention will be examined in the following four specific aims: 1) Method for Quantitative Mapping of DNA Damage Sites (Damage-seq) across the Whole Human Genome; 2) Method for Quantitative Mapping of Excision Repair (XR-seq) of the Whole Human Genome; 3) Genome-wide Analysis of Adduct Formation and Repair as a Function of Differentiation, Cell Cycle, and Chromatin States; and 4) Genome-wide Analysis of Adduct Formation and Repair in Human Biospecimens. The novel methods that we recently developed and will further optimize for mapping damage formation and repair will be used throughout this work. This proposal is innovative because it provides a new and unparalleled approach for characterizing DNA damage induced by environmental carcinogens and anti-cancer drugs. The proposed research is significant because it is expected to significantly expand our understanding of DNA damage formation and repair in the human genome at an unprecedented level of resolution. Ultimately, this knowledge has the potential to improve the prevention strategies for environmental carcinogenesis and to lead to the development of new tools for diagnosing and treating human cancer.

项目概要/摘要许多环境致癌物和抗癌药物在基因组 DNA 中形成大量碱基加合物。然而，这些病变在整个人类基因组中的精确位置尚不清楚，而且影响这些病变的因素也不清楚。使用目前可用的方法很难研究对损伤形成和修复的影响。损伤和修复的基因组位置强烈影响病理状况的发生，有需要新的方法来绘制整个基因组的损伤和修复事件。我们研究计划的目标是更好地了解核苷酸切除修复系统如何针对该特定提案的目的是进一步开发和应用。用于绘制致癌物和化疗诱导的 DNA 损伤形成和修复全程的新工具基因组并确定影响 DNA 损伤诱导和效率的关键因素我们团队在 DNA 领域的背景和专业知识。修复酶学和基因组学使我们有独特的资格来解决这个问题，对于这个提案，我们将。专注于识别环境致癌物形成的DNA碱基损伤的精确位置紫外线 (UV) 光和苯并[a]芘以及我们最近开发的铂基癌症化疗。我们称之为 Damage-seq 和 XR-seq 的独特测序技术可提供高分辨率 DNA 整个人类基因组中损伤形成和修复的序列信息。拟议研究的基本原理是绘制损坏和修复图的能力可能会揭示意想不到的信息特定基因组位点的环境致癌物、诱变和人类疾病之间的联系提出了诊断和治疗人类癌症的新策略。癌症风险和预防将在以下四个具体目标中进行检查： 1）定量方法整个人类基因组的 DNA 损伤位点图谱 (Damage-seq)；2) 定量方法；全人类基因组的切除修复（XR-seq）图谱；3）加合物的全基因组分析；形成和修复作为分化、细胞周期和染色质状态的函数；4) 全基因组人类生物样本中加合物形成和修复的分析我们最近的新方法。已开发并将进一步优化绘制损伤形成和修复图，将在整个工作中使用。该提案具有创新性，因为它提供了一种新的、无与伦比的方法来表征 DNA 损伤由环境致癌物和抗癌药物诱发的研究具有重要意义。预计将显着扩展我们对人类基因组中 DNA 损伤形成和修复的理解最终，这些知识有可能改善预防工作。环境致癌策略并导致诊断和诊断新工具的开发治疗人类癌症。