Uracil DNA glycosylases in herpesvirus pathogenesis and DNA mutation

尿嘧啶 DNA 糖基化酶在疱疹病毒发病机制和 DNA 突变中的作用

基本信息

批准号：
8683433
负责人：
Laurie T Krug
金额：
$ 21.07万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8683433
关键词：
Activities of Daily Living Acute Address Animal Model Antibodies Antibody Repertoire B-Lymphocytes Base Excision Repairs Burkitt Lymphoma Cells Chromosomal Instability Chromosomal translocation Chromosomes Chronic Complement Cytidine Deaminase DNA DNA Sequence Rearrangement DNA biosynthesis Data Defect Enzymes Equilibrium Etiology Event Frequencies Gene Mutation Generations Genes Genome Stability Genomics Growth Herpesviridae Human Herpesvirus 4 Human Herpesvirus 8 Immunity Immunoglobulin Class Switching Immunoglobulin Genes Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Immunoglobulins In Vitro Infection Investigation Lead Left Lesion Lung Lymphoma Lymphomagenesis Malignant Neoplasms Mission Molecular Mus Mutation National Cancer Institute National Institute of Allergy and Infectious Disease Oncogenes Oncogenic Outcome Pathogenesis Pathologic Mutagenesis Pathology Pathway interactions Play Prevention Process Recombinants Reporting Risk Role Simplexvirus Site Somatic Mutation Staging Terminator Codon Testing Tissues Uracil Viral Viral Genome Viral Pathogenesis Virus Virus Diseases Virus Latency activation-induced cytidine deaminase c-myc Genes cancer risk gammaherpesvirus glycosylation in vivo insight lytic replication mouse model new therapeutic target novel pathogen public health relevance reactivation from latency repaired uracil-DNA glycosylase viral DNA

项目摘要

DESCRIPTION (provided by applicant): Uracil DNA glycosylase (UNG) is an enzyme that removes misincorporated and mutagenic uracils, leaving an abasic site typically repaired by the host base excision repair pathway. Each herpesvirus encodes a viral UNG, but we know little regarding the function of this highly conserved gene in the virus lifecycle. Studies indicate that herpesvirus vUNGs interact with components of the viral DNA replication machinery and promote late stage replication events in primary or quiescent cells. The vUNG of herpes simplex virus has been reported to enhance herpes simplex virus latency in mice, but the role of vUNG in a full pathogenic course of gammaherpesvirus infection in a natural host has not been reported. The gammaherpesviruses Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus, and the mouse model pathogen murine gammaherpesvirus 68 establish latency in immunoglobulin class-switched B cells; infection can lead to immortalization and transformation of B cells. Host UNG2 activity is required for generating the diverse antibody repertoire of B cells, but also triggers chromosome translocations that are the etiology of lymphomas. Thus, alterations of uracil glycoslyase activity may tip the balance between immunity and malignancy. This proposal is to understand how the UNGs encoded by the gammaherpesviruses promote viral pathogenesis and impact the B cell antibody repertoire and lymphomagenesis of the host. In Aim 1, the impact of viral and host UNG on promoting the integrity of the viral genome in the process of lytic replication will be determined. In addition, we will examine changes in the pathogenesis of MHV68¿vUNG in the presence or absence of host UNG2 to determine the contribution of viral and host UNG to replication, latency, and reactivation in vivo. In Aim 2, we will address whether viral UNG promotes mutagenic outcomes such as immunoglobulin gene class-switch recombination and somatic hypermutation, off-target mutations in oncogenes, or translocations such as c-myc/Ig translocations that define EBV+ Burkitt's lymphoma. Our studies might uncover an interaction of viral UNG with the host cytidine deaminase AID that will provide critical insight regarding the molecular etiology of ¿HV cancers.

描述（由申请人提供）：尿嘧啶 DNA 糖基化酶 (UNG) 是一种酶，可去除错误掺入和诱变的尿嘧啶，留下通常通过宿主碱基切除修复途径修复的脱碱基位点。每种疱疹病毒都编码病毒 UNG，但我们对其了解甚少。研究表明，疱疹病毒 vUNG 与病毒 DNA 复制机制的组成部分相互作用，并促进后期复制。据报道，单纯疱疹病毒的 vUNG 可以增强小鼠中单纯疱疹病毒的潜伏期，但 vUNG 在自然宿主中伽马疱疹病毒感染的完整致病过程中的作用尚未见报道。 -巴尔病毒、卡波西肉瘤相关疱疹病毒和小鼠模型病原体鼠伽马疱疹病毒 68 在免疫球蛋白类别转换中建立潜伏期B 细胞；感染可导致 B 细胞永生化和转化。宿主 UNG2 活性是产生 B 细胞的多种抗体库所必需的，但也会引发染色体易位，从而导致淋巴瘤的病因。该提案旨在了解伽马疱疹病毒编码的 UNG 如何促进病毒发病机制并影响 B 细胞抗体库和淋巴瘤发生。在目标 1 中，将确定病毒和宿主 UNG 在裂解复制过程中对促进病毒基因组完整性的影响。此外，我们将检查 MHV68 发病机制的变化。在存在或不存在宿主 UNG2 的情况下检测 vUNG，以确定病毒和宿主 UNG 对体内复制、潜伏和重新激活的贡献。在目标 2 中，我们将讨论病毒 UNG 是否会促进突变结果，例如免疫球蛋白基因类别转换重组和突变。体细胞超突变、癌基因脱靶突变或定义 EBV+ 伯基特淋巴瘤的 c-myc/Ig 易位等易位。揭示病毒 UNG 与宿主胞苷脱氨酶 AID 的相互作用，这将为 ¿ 的分子病因学提供重要见解高压癌症。