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

摘要/项目总结 由真菌黄曲霉和寄生曲霉产生的黄曲霉毒素是众所周知的 环境致癌物导致突变并最终导致肝细胞癌（HCC）， 是全球癌症死亡的主要原因。长期从食物中摄入黄曲霉毒素B1（AFB1）， 致突变的黄曲霉毒素和慢性感染B型肝炎病毒（HBV）或丙型肝炎病毒（HCV）是 这是HCC发展的两个主要病因因素。核苷酸切除修复是修复机制 通过该方法将由AFB1诱导的大体积病变从基因组中去除。尽管我们在这方面取得了进展， AFB1-DNA加合物的知识，大体积DNA损伤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 本项目的目的是更好地了解AFB1诱导的DNA损伤形成和修复的动力学 导致人类肝脏突变。这一特定提案的总体目标是， 实现我们长期目标的步骤是将生物化学、遗传学、内收神经节和计算神经节联合收割机 研究组蛋白修饰和三维（3D）基因组组织对 探讨黄曲霉毒素B1（AFB1）诱导的DNA损伤形成和修复，以及AFB1-DNA之间的相关性 AFB1在人HCC中的加合物谱或修复效率和突变谱。我们的核心假设是 人肝突变与AFB1诱导的DNA损伤形成和/或修复相关 事件，这是受组蛋白修饰和3D基因组组织。我们提出两个具体的 目的是检验我们的假设，并实现目标：1）!黄曲霉毒素B1诱导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基因组结构的关系 (Aim1、K99和R00相）。2)黄曲霉毒素B1-DNA加合物光谱与修复的相关性研究 黄曲霉毒素B_1在人肝癌（Aim2，R00期）中的作用和突变谱我们期待以下内容 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;确定三维基因组组织对AFB1-DNA加合物形成和修复的影响 AFB1诱导的DNA损伤热点和修复冷点的鉴定 AFB1-DNA加合物光谱或修复效率与 人肝癌中黄曲霉毒素B1的突变谱这项拟议中的研究意义重大，因为它将提供见解 AFB1相关HCC的发展，改善预防策略并开发更好的治疗方法， HCC。

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.