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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：
9322347
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/9322347
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 DNA mapping 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 Pathogenicity Pathologic Patients Physiological Platinum Positioning Attribute Predisposition Prevention strategy Public Health 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 carcinogenicity 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.

项目总结/文摘