Cytosine Deamination Adducts and Cancer Etiology

胞嘧啶脱氨加合物和癌症病因学

• 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
• 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

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损伤会导致包括癌症在内的人类遗传病。外源化学物质与内源活性物质 分子会破坏DNA碱基，形成“加合物”。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。在人类癌症中观察到的突变图景是 由C：G向T主导：一种过渡性突变。这些突变的一个主要原因是水解性脱氨。 将DNA中的胞嘧啶和胞嘧啶类似物与其相应的尿嘧啶类似物结合起来，产生一类胞嘧啶 脱氨加成，徐。事实证明，像XU这样的内源DNA加合物更难研究，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 还有纸巾。在本申请中，我们描述了创新的新方法，这些方法将允许最终识别 徐使用质谱学方法在DNA中加成。此外，我们将测量形成和修复的 这些加合物位于已知的致癌突变热点，在正常人类细胞和全基因组中 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徐， 发炎和患病的标本。这里提出的研究将提供一种前所未有的对 这类重要但未被充分研究的DNA加合物是在DNA序列水平上的。评选结果 拟议的研究可能会导致临床上有用的方法来检查一个 给定的组织，并提供关于损害进展到何种程度的估计 肿瘤。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 减少癌症发病率并提供更早的检测。