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损伤导致了包括癌症在内的人类遗传疾病。外源性化学物质和内源性活性物质