Defining the regulation of double-strand DNA break repair by HIV Vpr

定义 HIV Vpr 对双链 DNA 断裂修复的调节

• 批准号: 10391452
• 负责人: Oliver I Fregoso
• 金额: $ 37.16万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-21 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391452
• 关键词: Attenuated; BRCA1 gene; Biochemical; Biological Assay; Biology; Cell Cycle; Cell Cycle Arrest; Cells; Chromatin; Clinical; Complex; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Single Strand Break; DNA Viruses; DNA biosynthesis; Data; Dependence; Developing Countries; Development; Drug usage; Ensure; Genes; Genome; Genotoxic Stress; Goals; HIV; HIV-1; Health; Heart; Human; Hypersensitivity; Impairment; In Vitro; Individual; Knowledge; Lentivirus; Ligation; Malignant Neoplasms; Malignant neoplasm of ovary; Mass Spectrum Analysis; Mediating; Molecular; Molecular Biology; Mutagens; Natural Immunity; Nonhomologous DNA End Joining; Orthologous Gene; Pathogenesis; Pathway interactions; Peripheral Blood Mononuclear Cell; Phenotype; Primate Lentiviruses; Property; Proteins; Proteomics; RNA Viruses; Regulation; Repression; Research; Role; Signal Transduction; Substrate Specificity; Techniques; Testing; Therapeutic; Viral; Virus; Virus Replication; Work; antiretroviral therapy; base; drug repurposing; ds-DNA; homologous recombination; human disease; in vivo; malignant breast neoplasm; monocyte; novel; novel therapeutics; protein protein interaction; recombinational repair; recruit; repaired; response; success; therapeutic target; ubiquitin ligase; vpr Genes

PROJECT SUMMARY / ABSTRACT HIV presents a major obstacle to human health, particularly in developing nations. Large strides have been made in understanding the basic molecular biology of HIV, which have led to advances in the development and success of antiretroviral therapies. Yet despite this knowledge, there are still many aspects of HIV biology which we do not understand. If we are to ever truly cure individuals of HIV, we must first fully understand the molecular mechanisms of viral replication to develop novel therapies that take advantage of essential steps in this lifecycle. One such aspect of HIV biology that has remained a mystery despite decades of research is the accessory gene Vpr. Vpr is evolutionarily conserved and important for pathogenesis in vivo, yet no clear role for Vpr in viral replication has been defined. An emerging property of Vpr-associated phenotypes is engagement of the DNA damage response (DDR). The DDR is a signaling cascade that is vital to ensuring the fidelity of the host genome in the presence of genotoxic stress. Growing evidence has emphasized the importance of both activation and repression of the host DDR by diverse DNA and RNA viruses. However, precisely how and why Vpr engages the DDR is unclear. We have recently begun to bridge this gap in knowledge by identifying that Vpr both activates and represses the DDR at multiple steps. Specifically, we have found that Vpr represses the ability of the cell to repair double- strand DNA breaks via homologous recombination (HR) and non-homologous end joining (NHEJ). Based on our preliminary data, we hypothesize that repression of double-strand DNA break repair is central to the primary function of Vpr. Moreover, we propose that the inability of Vpr-expressing cells to repair damaged DNA represents a tractable means to selectively deplete HIV+ cells via synthetic lethality with genotoxic agents that induce low levels of additional DNA damage. We will take a combined molecular, proteomic, and evolutionary approach to directly test our hypotheses. Success of our proposed research will define the primary role of Vpr, it will elucidate how the DDR regulates HIV replication, and it will provide a novel means to treat HIV+ individuals and clear infected cells.

项目摘要/摘要