Cytosine Deamination Adducts and Cancer Etiology

胞嘧啶脱氨加合物和癌症病因学

基本信息

批准号：
10592257
负责人：
Lawrence C Sowers
金额：
$ 40.64万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10592257
关键词：
Automobile Driving Base Pairing Biological Assay Cancer Etiology Cancer cell line Carcinogens Cell Line Cells Chemicals Clinical Codon Nucleotides CpG dinucleotide Cytosine DNA DNA Adduction DNA Adducts DNA Damage DNA Maintenance DNA Repair DNA Sequence DNA Sequence Alteration DNA biosynthesis DNA-Directed DNA Polymerase Deamination Defect Development Disease Early Diagnosis Enzymes Frequencies Genetic Genetic Diseases Human Human Cell Line Human Genetics Human Genome Incidence Inflammation Location Malignant Neoplasms Maps Mass Spectrum Analysis Measures Mediating Methods Methylation Mutate Mutation Normal Cell Oligonucleotides Polymerase Positioning Attribute Reactive Oxygen Species Recording of previous events Research Resolution Specimen Sum TP53 gene The Cancer Genome Atlas Time Tissues Water adduct analytical method base cytosine analog deep sequencing genome-wide halouracil human DNA human disease human tissue improved innovation novel strategies oxidation repaired stable isotope transition mutation tumor uracil analog

项目摘要

DNA damage drives human genetic disease including cancer. Exogenous chemicals and endogenous reactive molecules can damage DNA bases forming “adducts”. Unrepaired DNA adducts can block DNA synthesis or miscode during polymerase-mediated replication. The landscape of mutations observed in human cancers is dominated by C:G to T:A transition mutations. A major cause of these mutations is the hydrolytic deamination of cytosine and cytosine analogs in DNA to their corresponding uracil analogs, generating a class of cytosine deamination adducts, xU. Endogenous DNA adducts such as xU have proven more difficult to study due to the similarity of these adducts to normal DNA constituents as well as their formation in normal, unperturbed cells and tissues. In this application, we describe innovative new approaches that will allow definitive identification of xU adducts in DNA using mass spectrometry methods. Further, we will measure the formation and repair of such adducts at known cancer-driving mutational hotspots and genome-wide in both normal human cells and cells with known repair defects. We will also examine xU in discard human tissues representing normal, inflamed and diseased specimens. The studies proposed here will provide an unprecedented examination of this important but understudied class of DNA adducts at the level of DNA sequence. The results of the proposed studies could potentially result in clinically useful approaches to examine the damage history of a given tissue, and provide an estimate as to how far the damage had progressed toward the development of tumors. The anticipated results will shed new light on cancer etiology and potentially direct approaches to reduce cancer incidence and provide earlier detection.

DNA损害推动了包括癌症在内的人类遗传疾病。外源化学物质和内源性反应性分子会损害形成“加合物”的DNA碱基。未修复的DNA加合物可以阻止DNA合成或聚合酶介导的复制过程中的错误代码。在人类癌症中观察到的突变的景观是由C：G到T：过渡突变主导。这些突变的主要原因是水解死亡 DNA中与相应尿嘧啶类似物中的胞嘧啶和胞嘧啶类似物的生成一类胞嘧啶脱氨基加合物，Xu。事实证明，由于XU等内源性DNA加合物，由于这些加合物对正常DNA构建体的相似性以及它们在正常的，不受干扰的细胞中的形成和组织。在此应用中，我们描述了创新的新方法，这些方法将允许确定使用质谱法在DNA中的XU加合物。此外，我们将测量在正常人类细胞和具有已知修复缺陷的细胞。我们还将检查代表正常的人体组织中的XU，发炎和解散的标本。此处提出的研究将对在DNA序列水平上，这种重要但可以理解的DNA加合物类别。结果拟议的研究可能会导致临床上有用的方法检查A的损伤历史给定的组织，并提供了损害在发展中的发展的估计肿瘤。预期的结果将为癌症病因和潜在的直接方法提供新的启示降低癌症的发病率并提供早期检测。