Biological Consequences and Repair of Alkylated Thymidine Lesions

烷基化胸苷损伤的生物学后果和修复

基本信息

批准号：
9186451
负责人：
Yinsheng Wang
金额：
$ 34.2万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-05 至 2019-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9186451
关键词：
Alkylating Agents Alkylation Base Excision Repairs Biochemical Biological Biological Assay Bypass Cells Chemistry Chemotherapy-Oncologic Procedure DNA DNA Adducts DNA Alkylation DNA Repair DNA biosynthesis DNA lesion DNA-Directed DNA Polymerase ERCC1 gene Environmental Exposure Escherichia coli Etiology Genetic Transcription Glycosides Goals Health Housing Human Induced Mutation Knowledge Lead Lesion Lymphocyte Mainstreaming Malignant Neoplasms Mammalian Cell Mass Spectrum Analysis Measures Metabolism Methods Minor Groove Molecular Molecular Biology Mutagenesis Nucleosides Nucleotide Excision Repair Oligodeoxyribonucleotides Organic Chemistry Orthologous Gene Outcome Pathway interactions Positioning Attribute Process Reporting Research Risk Risk Factors Role Sampling Shuttle Vectors Site Stable Isotope Labeling Thymidine Tissues Transcription-Coupled Repair XPA gene adduct alkyl group base cancer chemoprevention chemotherapeutic agent cigarette smoking environmental tobacco smoke exposure exposed human population gene repair genetic information human disease innovation loss of function novel novel strategies nucleobase public health relevance repaired

项目摘要

DESCRIPTION (provided by applicant): Environmental exposure and endogenous metabolism both give rise to the alkylation of DNA, and DNA alkylation represents the major mechanism of action for a number of commonly prescribed cancer chemotherapeutic agents. Thus, assessing how alkylated DNA lesions compromise the flow of genetic information by altering the efficiency and fidelity of DNA replication and transcription and how these lesions are repaired will provide important knowledge for understanding the implications of DNA alkylation in the etiology for developing human diseases. Such knowledge will also form the basis for developing better strategies for cancer chemotherapy. The emphasis of this application is placed on a group of alkylated thymidine lesions which have been shown to persist in mammalian tissues or have been detected at substantially elevated levels in lymphocyte samples of humans exposed to cigarette smoke. We will employ an innovative and multi- pronged approach, including synthetic organic chemistry, mass spectrometry-based bioanalytical chemistry, and molecular biology to achieve a molecular-level understanding about how the under-investigated group of alkylated thymidine lesions impede DNA replication and transcription in cells, and induce mutations in these processes. We will also assess the implications of nucleotide excision repair and base excision repair pathways in the repair of these lesions in cells. The outcome of the proposed research will bring our understanding of this largely overlooked group of alkylated DNA lesions to a significantly higher level.

描述（由申请人证明）：环境暴露和内源性代谢都会引起DNA的烷基化，并且烷基化对许多常规癌症化学治疗剂的作用机理构成了作用机制。 DNA的细胞和转录以及这些病变的方式修复将提供理解DNA烷基化在病因学上的含义。，包括合成有机化学，基于质谱的L化学和分子生物学，以了解分子级别的理解，这些理解含量不足的烷基化病变群暗示细胞中的烷基化病变和转录。拟议研究的Exciss基础Xcision修复途径在拟议的研究结果中，这将使这种大量超过的基团烷基化NA病变达到更高的水平。