DNA Adduct Detection and Repair in Mammalian Cells

哺乳动物细胞中 DNA 加合物的检测和修复

基本信息

批准号：
10653232
负责人：
AZIZ SANCAR
金额：
$ 55.66万
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：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653232
关键词：
Affect Aflatoxins Age Aging Antineoplastic Agents Aromatic Polycyclic Hydrocarbons Aspergillus Benzo(a)pyrene Cancer Etiology Carcinogens Cells Chemicals Cisplatin Coal Tar Colorectal Cancer DNA DNA Adduction DNA Adducts DNA Damage DNA Repair DNA Repair Enzymes DNA Sequence DNA analysis DNA lesion DNA mapping Data Detection Development Diagnosis Diethylnitrosamine Disease Effectiveness Environmental Carcinogens Excision Experimental Animal Model Experimental Models Fluorenes Food Genome Genome Mappings Genomics Goals Human Human Cell Line Human Genome Industrial Waste Knowledge Laboratories Link Location Malignant Neoplasms Mammalian Cell Maps Meat Melphalan Methods Mission Modeling Mus Mutagenesis Mutagens Nucleotide Excision Repair Nucleotides Organ Outcome Pathogenicity Patients Positioning Attribute Predisposition Prevention strategy Primary carcinoma of the liver cells Public Health Regimen Research Research Personnel Resolution Role Site Source Surgical incisions System Technology Therapeutic Therapeutic Effect Time Tissues Tobacco smoke United States National Institutes of Health Work Xenograft procedure adduct anti-cancer base cancer therapy carcinogenesis cell injury chemotherapy cigarette smoke comparative consumer product design environmental carcinogenesis genome-wide genomic locus genomic predictors glycosylation holistic approach improved in vivo innovation mammalian genome metastatic colorectal mouse model novel oxidation oxidative damage pre-clinical prevent programs repair enzyme repaired side effect tool ultraviolet damage whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Numerous endogenous agents, environmental carcinogens, and anti-cancer drugs produce bulky base adducts in the genome. It is expected that the location of these adducts is non-random and that their locations dictate their pathogenic or therapeutic effects as well as their susceptibility to DNA repair enzymes that modulate these effects. The long-term goal of our research program is to better understand DNA damage and repair at the genomic level to aid in predicting and potentially preventing DNA adduct-induced carcinogenesis as well as to design efficient chemotherapeutic regimens with minimal side effects. The objective of this particular proposal is to use our novel adductomic-mapping methods (Damage-seq and XR-seq) to locate the exact positions of DNA lesions in the mammalian genome and the exact positions of DNA incisions performed by the nucleotide excision repair enzyme system that removes the DNA damage. The rationale for the proposed research is that mapping damage and repair may reveal unexpected links between environmental carcinogens, mutagenesis, disease and ageing. We will accomplish this goal by carrying out the following three specific aims: 1) Genomic Single- nucleotide Resolution Analysis of DNA Damage by Endogenous Agents; 2) Genome-wide Single Nucleotide Resolution Maps of DNA Damage and Repair by Exogenous Carcinogens; 3) Genome-wide Damage and Repair Maps of Anticancer Drugs. For this proposal, we will focus on identifying the precise locations and removal of DNA base damage formed endogenously (glycosylation, oxidative damage) and damage caused by environmental carcinogens (aflatoxin, diethylnitrosamine) and anticancer drugs (cisplatin, melphalan). Methods that we developed and further optimized for mapping damage formation and repair will be used throughout this work. This proposal is innovative because of these unique sequencing technologies that provide high-resolution DNA sequence information on the formation and repair of damage throughout the entire genome and provide an unparalleled approach for characterizing endogenous DNA damage as well as damage induced by environmental carcinogens and anti-cancer drugs. The proposed research is significant because it will address the question of the role of DNA damage by endogenous agents (glycosylation) of various tissues and its overall contribution to aging by these methods developed in our laboratory which have unprecedented sensitivity for genome-wide mapping at single nucleotide resolution in different organs. In addition, the proposed research will expand our understanding of DNA damage formation and repair in the human genome at an unprecedented level of detail regarding genomic damage formed endogenously and by environmental carcinogens and anticancer drugs. 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 cancer.

项目概要/摘要许多内源性物质、环境致癌物和抗癌药物会产生大量的碱加合物在基因组中。预计这些加合物的位置是非随机的，并且它们的位置决定它们的致病或治疗作用以及对调节这些作用的 DNA 修复酶的敏感性影响。我们研究计划的长期目标是更好地了解 DNA 损伤和修复基因组水平有助于预测和潜在预防 DNA 加合物诱导的致癌作用以及设计副作用最小的有效化疗方案。该特定提案的目标是使用我们新颖的内合组作图方法（Damage-seq 和 XR-seq）来定位 DNA 的确切位置哺乳动物基因组中的损伤以及通过核苷酸切除进行的 DNA 切口的确切位置修复酶系统，消除DNA损伤。拟议研究的基本原理是映射损伤和修复可能会揭示环境致癌物、诱变、疾病和老化。我们将通过实现以下三个具体目标来实现这一目标：1）基因组单- 内源性物质造成的 DNA 损伤的核苷酸解析分析； 2) 全基因组单核苷酸外源性致癌物造成的 DNA 损伤和修复的分辨率图； 3）全基因组损伤与修复抗癌药物地图。对于这个提案，我们将重点关注确定精确位置并移除内源性形成的 DNA 碱基损伤（糖基化、氧化损伤）和由外源性损伤引起的损伤环境致癌物（黄曲霉毒素、二乙基亚硝胺）和抗癌药物（顺铂、美法仑）。方法我们为绘制损伤形成和修复而开发并进一步优化的工具将在整个过程中使用工作。该提案具有创新性，因为这些独特的测序技术可提供高分辨率有关整个基因组损伤形成和修复的 DNA 序列信息，并提供无与伦比的方法来表征内源性 DNA 损伤以及由环境致癌物和抗癌药物。拟议的研究意义重大，因为它将解决各种组织的内源性物质（糖基化）对 DNA 损伤的作用及其总体问题我们实验室开发的这些方法对衰老的贡献具有前所未有的敏感性不同器官中单核苷酸分辨率的全基因组图谱。此外，拟议的研究将以前所未有的方式扩展我们对人类基因组中 DNA 损伤形成和修复的理解关于内源性和环境致癌物形成的基因组损伤的详细程度抗癌药物。最终，这些知识有可能改进预防策略环境致癌并导致诊断和治疗癌症的新工具的开发。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

In vitro DNA repair genomics using XR-seq with Escherichia coli and mammalian cell-free extracts.

使用 XR-seq 与大肠杆菌和哺乳动物无细胞提取物进行体外 DNA 修复基因组学。

DOI：
发表时间：
2023-10-24
期刊：
影响因子：
11.1
作者：
Cao, Xuemei;Kose, Cansu;Selby, Christopher P;Sancar, Aziz
通讯作者：
Sancar, Aziz

Circadian clock, carcinogenesis, chronochemotherapy connections.

昼夜节律时钟、致癌作用、计时化疗的联系。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Yang, Yanyan;Lindsey;Vaughn, Courtney M;Selby, Christopher P;Cao, Xuemei;Liu, Zhenxing;Hsu, David S;Sancar, Aziz
通讯作者：
Sancar, Aziz

Global repair is the primary nucleotide excision repair subpathway for the removal of pyrimidine-pyrimidone (6-4) damage from the Arabidopsis genome.

全局修复是从拟南芥基因组中去除嘧啶-嘧啶酮 (6-4) 损伤的主要核苷酸切除修复子途径。

DOI：
发表时间：
2024-02-08
期刊：
影响因子：
4.6
作者：
Kaya, Sezgi;Erdogan, Dugcar Ebrar;Sancar, Aziz;Adebali, Ogun;Oztas, Onur
通讯作者：
Oztas, Onur

Comparative analyses of two primate species diverged by more than 60 million years show different rates but similar distribution of genome-wide UV repair events.

对两种分化超过 6000 万年的灵长类物种的比较分析显示，全基因组紫外线修复事件的速率不同，但分布相似。

DOI：
发表时间：
2021-08-06
期刊：
影响因子：
4.4
作者：
Akkose, Umit;Kaya, Veysel Ogulcan;Lindsey;Karagoz, Zeynep;Brown, Adam D;Larsen, Peter A;Yoder, Anne D;Sancar, Aziz;Adebali, Ogun
通讯作者：
Adebali, Ogun

Preservation of circadian rhythm in hepatocellular cancer.

维持肝细胞癌的昼夜节律。