Role of Aflatoxin-induced DNA Damage Formation and Repair in Hepatic Mutagenesis

黄曲霉毒素诱导的 DNA 损伤形成和修复在肝突变中的作用

• 批准号: 10011805
• 负责人: Wentao Li
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-03 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011805
• 关键词: 3-Dimensional; Affect; Aflatoxin B1; Aflatoxins; Aspergillus; Aspergillus flavus; Biochemistry; Cancer Etiology; Carcinogens; Cessation of life; Chronic; DNA Adduction; DNA Damage; DNA Repair; DNA lesion; Data; Data Set; Development; Diet; Environmental Carcinogens; Etiology; Event; Excision; Excision Repair; Exposure to; Foundations; Genes; Genetic; Genome; Goals; Hepatic; Hepatitis B; Hepatitis C virus; Histone Acetylation; Hot Spot; Human; Kinetics; Knowledge; Lesion; Malignant Neoplasms; Methods; Mutagenesis; Mutation; Mutation Spectra; Nucleotide Excision Repair; Nucleotides; Organism; Outcome; Pharmaceutical Preparations; Phase; Positioning Attribute; Prevention strategy; Primary carcinoma of the liver cells; Research; Research Personnel; Resolution; Role; Spottings; Technology; Testing; Virus Diseases; aflatoxin B1-DNA adduct; carcinogenicity; chronic infection; fungus; genome-wide; genome-wide analysis; histone modification; improved; innovation; insight; novel; repaired; synergism

ABSTRACT / PROJECT SUMMARY Aflatoxin, produced by the fungi Aspergillus flavus and Aspergillus parasiticus, is a well-known environmental carcinogen that causes mutations and ultimately leads to hepatocellular carcinoma (HCC), one of the leading causes of cancer deaths worldwide. Chronic dietary exposure to aflatoxin B1 (AFB1), the most mutagenic aflatoxin, and chronic infections with the hepatitis B virus (HBV) or hepatitis C virus (HCV) are the two major etiological factors for the development of HCC. Nucleotide excision repair is the repair mechanism by which the bulky lesions induced by AFB1 are removed from the genome. Despite the progress in our knowledge of the AFB1-DNA adduct, the formation and removal kinetics of the bulky DNA lesion throughout the genome and the factors affecting the damage formation and repair efficiency remain elusive. Our long-term goal of this project is to better understand how the kinetics of AFB1-induced DNA damage formation and repair contributes to human hepatic mutagenesis. The overall objective of this particular proposal, which is an initial step to achieve our long-term goal, is to combine biochemistry, genetics, adductomics and computational approaches to investigate effects of histone modifications and three-dimensional (3D) genome organization on AFB1-induced DNA damage formation and repair, and to determine the correlations between AFB1-DNA adduct spectra or repair efficiencies and mutational spectra of AFB1 in human HCC. Our central hypothesis is that human hepatic mutagenesis correlates with the AFB1-induced DNA damage formation and/or repair events, which are affected by histone modifications and 3D genome organization. We propose two specific aims to test our hypothesis and accomplish the objective: 1)! Genome-wide Analysis of AFB1-induced DNA Damage Formation and Repair Kinetics as a Function of Histone Modifications and 3D Genome Organization (Aim1, K99 and R00 phase). 2) Determine the Correlations Between AFB1-DNA Adduct Spectra or Repair Efficiencies and Mutational Spectra of AFB1 in Human HCC (Aim2, R00 phase). We expect the following outcomes: Determination of the effect of histone acetylation on AFB1-DNA adducts formation and repair efficiency; determination of the effect of 3D genome organization on AFB1-DNA adducts formation and repair efficiency; identification of AFB1-induced DNA damage hot spots and repair cold spots in cancer-associated genes; determination of the correlations between AFB1-DNA adduct spectra or repair efficiencies and mutational spectra of AFB1 in human HCC. The proposed research is significant because it will give insights into development of AFB1-associated HCC, improve prevention strategies and develop better treatment for HCC.

摘要 /项目摘要 真菌曲霉和寄生虫曲霉产生的黄曲霉毒素是众所周知的 引起突变并最终导致肝细胞癌（HCC）的环境致癌物，一个 全球癌症死亡的主要原因。慢性饮食暴露于黄曲霉毒素B1（AFB1），最多是 诱变的黄曲霉毒素和肝炎病毒（HBV）或丙型肝炎病毒（HCV）的慢性感染是 HCC发展的两个主要病因。核苷酸切除修复是修复机制 AFB1诱导的庞大病变从基因组中去除。尽管我们的进展取得了进步 了解AFB1-DNA加合物，整个笨重DNA病变的形成和去除动力学 基因组和影响损伤形成和修复效率的因素仍然难以捉摸。我们的长期 该项目的目标是更好地了解AFB1诱导的DNA损伤形成和修复的动力学如何 有助于人类肝诱变。该特定提议的总体目标，这是最初的 实现我们的长期目标的步骤是结合生物化学，遗传学，加合物学和计算 研究组蛋白修饰和三维（3D）基因组组织的影响的方法 AFB1诱导的DNA损伤形成和修复，并确定AFB1-DNA之间的相关性 AFB1在人HCC中的加合光谱或修复效率和突变光谱。我们的中心假设是 人类肝诱变与AFB1诱导的DNA损伤形成和/或修复有关 事件，受组蛋白修饰和3D基因组组织的影响。我们提出了两个特定的 旨在检验我们的假设并实现目标：1）！ AFB1诱导的DNA的全基因组分析 损伤形成和修复动力学与组蛋白修饰和3D基因组组织的关系 （AIM1，K99和R00阶段）。 2）确定AFB1-DNA加合物光谱或修复之间的相关性 AFB1在人HCC中的效率和突变光谱（AIM2，R00期）。我们期望以下 结果：确定组蛋白乙酰化对AFB1-DNA加合物形成和修复的影响 效率;确定3D基因组组织对AFB1-DNA加合物形成和修复的影响 效率;鉴定AFB1诱导的DNA损伤热点并修复与癌症相关的冷点 基因；确定AFB1-DNA加合物光谱或修复效率与维修效率和 AFB1在人HCC中的突变光谱。拟议的研究很重要，因为它将提供见解 发展与AFB1相关的HCC，改善预防策略并为 HCC。