Mechanisms of HTLV-1 p30 in Transcription and DMA Repair

通过对逆转录病毒的研究获得的见解确立了细胞生物学的基本范式，包括 淋巴细胞活化和增殖的机制。在P01 CA100730的项目1中，我们寻求继续 人类T淋巴细胞嗜T细胞病毒1型(HTLV-1)复杂逆转录病毒的基本问题 这会导致成人T细胞淋巴瘤/白血病(ATL)。HTLV-1编码典型的gag、pol和env基因 产物，以及在其Px区编码的独特基因。在这个高度协作的PPG中，我们开创了 HTLV-1蛋白在体内病毒复制和淋巴细胞激活中的作用 病毒传播和细胞转化的重要先兆。这个项目的重点是从 这些研究集中了我们对HTLV-1 Px ORF II编码的P30的研究。这 核/核仁蛋白与转录因子同源，含有G/SK共同乙酰化 网站。我们与Green、Ratner和Boris-Lawrie博士的合作研究(项目2、3、5，核心A、B和C) PPG提供的第一个证据表明，病毒需要P30来确定动物的感染，ACTS 作为一种转录因子，受到乙酰化的积极影响，并结合共激活因子的KIX结构域， P300。我们现在提供令人兴奋的新数据，这些数据表明P30参与了DMA损伤/修复信号，从而导致 细胞周期紊乱，并可能促进病毒整合。我们的数据表明HTLV-1在一部小说中使用了P30 调节细胞环境以利于细胞生存和平衡病毒反式激活的影响的方式 (例如，税收)，以允许病毒持续存在。在本PPG的下一阶段，我们将提供相互依赖的方法来 通过对Essential的比较测试确定HTLV-1 P30和HTLV-2 P28(项目2)的作用 转录和转录后控制参数。我们为此制定了明确的目标 项目1的竞争性更新：1)定位HTLV-1 P30的重要结构基序， T淋巴细胞的转录调控和DNA损伤/修复信号，2)决定翻译后的作用 HTLV-1 P30介导的转录调控和DNA损伤/修复的研究进展 T淋巴细胞中的信号转导，以及3)测试在P30介导的转录中重要的结构基序 早期病毒表达时空分布中的调控和DNA损伤/修复信号 在带有Px ORF II选择性突变的HTLV-1分子克隆的兔身上。我们的长期目标是 了解逆转录病毒，如HTLV-1是如何改变T细胞生理的，从而深入了解 细胞转化的早期阶段和治疗干预的新靶点。

Insights gained through the study of retroviruses have established basic paradigms of cell biology, including mechanisms of lymphocyte activation and proliferation. In Project 1 of P01 CA100730 we seek to continue to investigate fundamental questions of Human T-lymphotropic Virus Type 1 (HTLV-1), a complex retrovirus that causes adult T-cell lymphoma/leukemia (ATL). HTLV-1 encodes typical gag, pol, and env gene products, and unique genes encoded in its pX region. In this highly collaborative PPG, we have pioneered the examination of the role of HTLV-1 proteins in viral replication in vivo and in lymphocyte activation, an important antecedent to virus transmission and cell transformation. The focus of this project emerged from these studies and concentrates our proposed studies on p30 encoded in pX ORF II of HTLV-1. This nuclear/nucleolar protein has homology to transcription factors and contains G/SK consensus acetylation sites. Our collaborative studies with Drs. Green, Ratner, and Boris-Lawrie (Projects 2, 3, 5, Cores A, B, & C) of this PPG provided the first evidence that p30 is required by the virus to establish infection in animals, acts as a transcription factor, is positively influenced by acetylation and binds the KIX domain of the co-activator, p300. We now provide exciting new data that implicate p30 in DMA damage/repair signaling that results in cell cycle perturbation and likely promote viral integration. Our data indicate that HTLV-1 uses p30 in a novel manner to modulate the cellular environment to favor cell survival and balances the influence of viral transactivation (i.e., Tax) to allow viral persistence. In our next phase of this PPG, we provide interdependent approaches to identify the roles of HTLV-1 p30 and HTLV-2 p28 (Project 2) by comparative testing of essential transcriptional and post-transcriptional control parameters. We have focused specific aims for this competitive renewal of Project 1 on: 1) Localize important structural motifs of HTLV-1 p30 that mediated transcriptional regulation and DNA damage/repair signaling in T lymphocytes, 2) Determine the role of posttranslation modifications in HTLV-1 p30 -mediated transcriptional regulation and DNA damage/repair signaling in T lymphocytes, and 3) Test structural motifs important in p30 -mediated transcriptional regulation and DNA damage/repair signaling in the spatial and temporal distribution of early virus expression in rabbits with HTLV-1 molecular clones with selective mutations in pX ORF II. Our long-term goal is to understand how retroviruses, like HTLV-1 alter T cell physiology and thereby gain insight into mechanisms of the early phases of cell transformation and new targets of therapeutic intervention.