Regulation of Gammaherpesviral Late Gene Expression

γ疱疹病毒晚期基因表达的调控

• 批准号: 9178643
• 负责人: Britt A Glaunsinger
• 金额: $ 37.03万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-11-13 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178643
• 关键词: Acquired Immunodeficiency Syndrome; Affinity; Antiviral Agents; Architecture; Binding; Biology; Cancer Etiology; Cells; Cercopithecine Herpesvirus 1; Code; Complex; Congenital Disorders; Cryoelectron Microscopy; DNA; DNA Polymerase II; DNA Viruses; DNA biosynthesis; DNA-Directed RNA Polymerase; Data; Disease; Double Stranded DNA Virus; Electron Microscopy; Eukaryota; Eukaryotic Cell; Gene Expression; Genes; Genetic Transcription; Grant; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 8; Hybrids; Imagery; Immunocompromised Host; Impairment; Individual; Infection; Late Gene Transcriptions; Late Promoters; Life; Life Cycle Stages; Light; Link; Malignant Neoplasms; Modeling; Molecular Mimicry; Mutation; Negative Staining; Patients; Polymerase; Population; Process; Proteins; Recruitment Activity; Regulation; Reporting; Role; TATA-Box Binding Protein; Transcription Coactivator; Transcriptional Regulation; Viral; Viral Genes; Viral Genome; Viral Proteins; Virion; Virus; Virus Assembly; Virus Replication; Visual; base; defined contribution; experimental study; gammaherpesvirus; high throughput screening; mammalian genome; member; mimicry; mutant; novel; novel virus; particle; pathogen; promoter; protein protein interaction; public health relevance; transcription factor

 DESCRIPTION (provided by applicant): Herpesviruses are endemic within the human population, and cause a wide range of life-threatening diseases. Members of the beta-herpesvirus (β-HV) and gamma-herpesvirus (γ-HV) subfamilies are extremely problematic in immunocompromised individuals, leading to severe congenital disorders and a variety of cancers. During the herpesviral replication cycle, viral genes are expressed temporally in an ordered cascade, with timing linked to appropriate life cycle stage needs. Following viral genome replication, a group of viral genes termed late genes (L) are robustly activated and produce proteins necessary for progeny virion assembly and egress. Mechanisms governing L gene expression in the β-HV and the γ-HV largely remain a mystery. However, shedding light on this aspect of herpesviral biology has become a high priority, in part due to recent discoveries demonstrating that mutants impaired in this final viral transcription cascade cannot produce progeny virions. An understanding of the regulatory features critical for L gene transcription may therefore reveal robust new targets for antiviral strategies. Our data demonstrate that late gene transcriptional regulation is unique, as it incorporates both molecular mimicry and selective recruitment of key host transcriptional machinery in a manner not previously observed in viral or host gene expression. Thus, the focus of this grant is to define the composition and regulation of this novel gene expression complex, as well as reveal how it may globally impact gene expression in infected cells.

 描述（由适用提供）：疱疹病毒在人口中是内在的，并引起广泛的威胁生命的疾病。在免疫功能低下的个体中，β-HEPESVIRUS（β-HV）和γ-HEPESVIRUS（γ-HV）的成员非常有问题，导致严重的先天性疾病和各种癌症。在疱疹病毒复制周期中，病毒基因在有序的级联反应中暂时表达，并与适当的生命周期阶段需求有关。病毒基因组复制后，一组称为晚期基因（L）的病毒基因被强烈激活，并产生的蛋白质对于进度的病毒体组装和出口所必需。控制β-HV和γ-HV中L基因表达的机制在很大程度上仍然是一个谜。然而，阐明疱疹病毒生物学的这一方面已成为一个很高的优先事项，部分原因是最近发现表明在最终病毒转录级联中受损的突变体无法产生进度病毒。因此，对L基因转录至关重要的调节特征的理解可能揭示了抗病毒策略的新目标。我们的数据表明，晚期基因转录调控是独一无二的，因为它既包含了分子模仿和选择性募集的关键宿主转录机制，却以先前在病毒或宿主基因表达中观察到的方式融合了。这是该赠款的重点是定义这种新型基因表达复合物的组成和调节，并揭示了它如何全球影响受感染细胞中的基因表达。