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：
10359784
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 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10359784
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 Adducts DNA Damage 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 Lead Light Location Malignant Neoplasms Maps Mass Spectrum Analysis Measures Mediating Methods 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 损伤会导致人类遗传疾病，包括癌症。分子会损伤 DNA 碱基，形成“加合物”，而未修复的 DNA 加合物会阻碍 DNA 合成或。聚合酶介导的复制过程中的错误编码是在人类癌症中观察到的突变情况。以 C:G 到 T:A 的过渡突变为主，这些突变的主要原因是水解脱氨作用。 DNA中的胞嘧啶和胞嘧啶类似物与其相应的尿嘧啶类似物的结合，产生一类胞嘧啶脱氨基加合物，xU 内源性 DNA 加合物（例如 xU）已被证明更难以研究，因为这些加合物与正常 DNA 成分的相似性以及它们在正常、未受干扰的细胞中的形成在此应用中，我们描述了创新的新方法，可以明确识别此外，我们将使用质谱方法测量 DNA 中 xU 加合物的形成和修复。这种加合物存在于已知的癌症驱动突变热点和正常人类细胞和全基因组范围内。我们还将检查代表正常的废弃人体组织中的 xU。这里提出的研究将对发炎和患病的标本进行前所未有的检查。这一类在 DNA 序列水平上重要但尚未得到充分研究的 DNA 加合物。拟议的研究可能会产生临床上有用的方法来检查损伤历史给定的组织，并提供有关损伤进展到何种程度的估计预期的结果将为癌症病因学和潜在的直接治疗方法提供新的线索。降低癌症发病率并提供早期检测。