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

• 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
• 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

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.

项目摘要/摘要 许多内源剂，环境致癌物和抗癌药产生庞大的基础加合物 在基因组中。预计这些加合物的位置是非随机的，它们的位置决定了 它们的致病性或治疗作用以及对调节这些修复酶的敏感性 效果。我们的研究计划的长期目标是更好地了解DNA损伤和维修 基因组水平有助于预测和可能预防DNA加合物诱导的致癌作用以及 设计有效的化学治疗方案，具有最小的副作用。这个特定建议的目的是 使用我们的新型辅助映射方法（损坏seq和xr-seq）来定位DNA的精确位置 哺乳动物基因组中的病变和核苷酸切除执行的DNA切口的精确位置 修复去除DNA损伤的酶系统。拟议研究的理由是映射 损害和维修可能会揭示环境致癌物，诱变，疾病和 老化。我们将通过执行以下三个特定目标来实现这一目标：1）基因组单一 - 内源性药物对DNA损伤的核苷酸分辨率分析； 2）全基因组单核苷酸 外源性致癌物的DNA损伤和修复的分辨率图； 3）全基因组损害和修复 抗癌药物的地图。对于此提案，我们将专注于确定确切位置和去除 DNA碱基损伤内源形成（糖基化，氧化损伤）和由 环境致癌物（黄曲霉毒素，二乙基硝基胺）和抗癌药（Cisplatin，Melphalan）。方法 我们将在此过程中开发并进一步优化用于映射损坏的形成和维修 工作。该建议具有创新性，因为这些独特的测序技术提供了高分辨率 DNA序列有关整个基因组损伤的形成和修复的信息，并提供 表征内源性DNA损伤以及造成的损害的无与伦比的方法 环境致癌物和抗癌药物。拟议的研究很重要，因为它将解决 内源性剂（糖基化）及其整体的内源性剂（糖基化）的DNA损伤作用的问题 通过在我们的实验室中开发的这些方法对衰老的贡献，这些方法对 在不同器官的单核苷酸分辨率下，全基因组映射。此外，拟议的研究将 扩展我们对人类基因组中DNA损伤形成和修复的理解 有关基因组损伤的细节水平，由环境致癌物和环境致癌物和 抗癌药。最终，这些知识有可能改善预防策略 环境致癌，并导致开发用于诊断和治疗癌症的新工具。

项目成果

Genome-wide analysis of 8-oxo-7,8-dihydro-2'-deoxyguanosine at single-nucleotide resolution unveils reduced occurrence of oxidative damage at G-quadruplex sites.

• DOI: 10.1093/nar/gkab1022
• 发表时间: 2021-12-02
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: An J;Yin M;Yin J;Wu S;Selby CP;Yang Y;Sancar A;Xu GL;Qian M;Hu J
• 通讯作者: Hu J

Genome-wide Excision Repair Map of Cyclobutane Pyrimidine Dimers in Arabidopsis and the Roles of CSA1 and CSA2 Proteins in Transcription-coupled Repair.

• DOI: 10.1111/php.13519
• 发表时间: 2022-05
• 期刊: PHOTOCHEMISTRY AND PHOTOBIOLOGY
• 影响因子: 3.3
• 作者: Kaya, Sezgi;Adebali, Ogun;Oztas, Onur;Sancar, Aziz
• 通讯作者: Sancar, Aziz

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

• DOI: 10.1073/pnas.2314233120
• 发表时间: 2023-10-24
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Cao, Xuemei;Kose, Cansu;Selby, Christopher P.;Sancar, Aziz
• 通讯作者: Sancar, Aziz

Nucleotide excision repair in Human cell lines lacking both XPC and CSB proteins.

• DOI: 10.1093/nar/gkad334
• 发表时间: 2023-07-07
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Lindsey-Boltz, Laura A.;Yang, Yanyan;Kose, Cansu;Deger, Nazli;Eynullazada, Khagani;Kawara, Hiroaki;Sancar, Aziz
• 通讯作者: Sancar, Aziz

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.

• DOI: 10.1186/s12864-021-07898-3
• 发表时间: 2021-08-06
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Akkose U;Kaya VO;Lindsey-Boltz L;Karagoz Z;Brown AD;Larsen PA;Yoder AD;Sancar A;Adebali O
• 通讯作者: Adebali O