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: 10252859
• 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/10252859
• 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; 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; dietary; 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 黄曲霉毒素是由黄曲霉和寄生曲霉产生的一种众所周知的毒素。 引起突变并最终导致肝细胞癌 (HCC) 的环境致癌物，一种 全球癌症死亡的主要原因。长期饮食接触黄曲霉毒素 B1 (AFB1) 致突变性黄曲霉毒素和乙型肝炎病毒 (HBV) 或丙型肝炎病毒 (HCV) 慢性感染是导致 HCC 发展的两个主要病因。核苷酸切除修复是修复机制 通过这种方法，AFB1 诱导的大量损伤将从基因组中去除。尽管我们的工作取得了进展 了解 AFB1-DNA 加合物、大体积 DNA 损伤的形成和去除动力学 基因组以及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 有助于人类肝脏突变。该特定提案的总体目标是初步 实现我们长期目标的一步是将生物化学、遗传学、加成组学和计算结合起来 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 人类 HCC 中 AFB1 的加合物谱或修复效率和突变谱。我们的中心假设是 人类肝脏突变与 AFB1 诱导的 DNA 损伤形成和/或修复相关 事件，受组蛋白修饰和 3D 基因组组织的影响。我们提出两个具体方案 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作为组蛋白修饰和 3D 基因组组织的函数 （Aim1、K99 和 R00 阶段）。 2) 确定 AFB1-DNA 加合物谱或修复之间的相关性 AFB1 在人类 HCC 中的效率和突变谱（Aim2，R00 期）。我们期望以下内容 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;识别癌症相关中 AFB1 诱导的 DNA 损伤热点和修复冷点 基因；确定 AFB1-DNA 加合物谱或修复效率之间的相关性 人类 HCC 中 AFB1 的突变谱。拟议的研究很重要，因为它将提供见解 参与 AFB1 相关 HCC 的发展，改进预防策略并开发更好的治疗方法 肝癌。