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

基本信息

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
项目类别：
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

项目摘要

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一种众所周知的毒素，由黄曲霉和寄生曲霉产生。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。