HTLV-1 Tax Disrupts DNA Damage Repair-Response Complexes

HTLV-1 Tax 破坏 DNA 损伤修复反应复合物

• 批准号: 7913928
• 负责人: OLIVER John SEMMES
• 金额: $ 10.55万
• 依托单位: EASTERN VIRGINIA MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913928
• 关键词: Adult; Adult Lymphoma; Arts; Binding; Biological Assay; Cell Cycle Checkpoint; Cell physiology; Cells; Characteristics; Classification; Clinical; Collaborations; Complex; Confocal Microscopy; DNA Damage; DNA Repair; Data; Development; Disease; Dissection; Environment; Genomic Instability; Genomics; Goals; Human Resources; Human T-lymphotropic virus 1; Individual; Infection; Intervention; Laboratories; Lead; Life; Literature; Mass Spectrum Analysis; Mediating; Microscopy; Modeling; Molecular; Molecular Biology; Molecular Virology; Morbidity - disease rate; Neoplasms; Neurodegenerative Disorders; Nuclear; Nuclear Protein; Nuclear Proteins; Outcome; Process; Progress Reports; Proteins; Proteomics; Regulation; Research; Research Personnel; Resources; Risk; Role; Source; Spinal Cord Diseases; Structure; System; T-Cell Leukemia; T-Lymphocyte; Taxes; Tertiary Protein Structure; Testing; Therapeutic Intervention; Tropical Spastic Paraparesis; Viral; Viral Proteins; Work; base; cellular targeting; design; insight; instrumentation; leukemogenesis; meetings; metaplastic cell transformation; mortality; new therapeutic target; novel; novel therapeutics; prevent; programs; protein complex; protein function; repaired; response; tax Gene Products

DESCRIPTION (provided by applicant): The Human T-Cell Leukemia Virus type 1 causes Adult T-Cell Leukemia and HTLV-Associated Myelopathy/Tropical Spastic Paraparesis. It is believed that transformation of the infected T-cell by the viral protein Tax results in disease. The process by which Tax mediates cellular transformation is not well understood but is thought to involve Tax-mediated cellular genomic instability. The objective of these studies is to uncover the mechanism by which Tax disrupts normal cellular DNA damage recognition-repair response, thus promoting genomic instability. We specifically hypothesize that Tax targets to and functionally disrupts a nuclear complex that regulates key aspects of cellular DNA damage response, repair recognition and checkpoint activation. We propose (and will confirm) that the nuclear complex targeted by Tax is the same "damage foci" described in the general literature as forming in response to DNA damage. We will use live-cell deconvolution and confocal microscopy to define the mechanism by which Tax targets this complex. The component make-up and physical characteristics of the Tax-containing complexes will be determined using sophisticated mass spectrometry based approaches. The structural and functional impact of Tax on these complexes will be revealed by a combination of quantitative proteomics and molecular functional assays. The successful completion of the studies described in this proposal will provide a mechanism by which expression of Tax results in genomic instability. Elucidation of this cause and effect model will contribute significantly to our understanding of HTLV-1-mediated disease.

描述(申请人提供)：人类T细胞白血病病毒1型导致成人T细胞白血病和HTLV相关性脊髓病/热带痉挛瘫痪。据认为，感染的T细胞通过病毒蛋白Tax的转化而导致疾病。税收调节细胞转化的过程尚未被很好地理解，但被认为涉及税收介导的细胞基因组不稳定。这些研究的目的是揭示税收扰乱正常细胞DNA损伤识别-修复反应，从而促进基因组不稳定的机制。我们特别假设，税收针对并在功能上扰乱一个核复合体，该复合体调节细胞DNA损伤反应、修复识别和检查点激活的关键方面。我们建议(并将证实)税收所针对的核复合体与一般文献中描述的针对DNA损伤而形成的“损伤焦点”是相同的。我们将使用活细胞去卷积和共聚焦显微镜来定义税收针对这种复合体的机制。含税络合物的组成和物理特征将使用复杂的基于质谱学的方法来确定。税收对这些复合体的结构和功能的影响将通过定量蛋白质组学和分子功能分析相结合的方式来揭示。本提案中描述的研究的成功完成将提供一种机制，通过该机制，税收的表达将导致基因组的不稳定。阐明这一因果模型将有助于我们理解HTLV-1介导的疾病。