MOLECULAR BIOLOGY OF THE DELTA AGENT

类病毒和类病毒病原体--尤其是病原体 对三角洲肝炎负有责任--提供大量RNA物种的例子 依赖于细胞组件的生命周期，创建 这些成分的潜在失衡和细胞病理学。几个 几年前，我们提出了一个1700碱基的基因组RNA的双域模型 Delta试剂，其中非编码RNA高度保守， 包含复制所需的大部分或全部功能域。 该模型得到了广泛的支持，非编码域得到了广泛的支持 命名为“类病毒”的域名，现在已知它包含： RNA裂解核酶活性，我们已经证明它包含一个共同的 基序和能够反式切割的；与一个 丰富的细胞RNA(SRP RNA)；两个可选的次要 结构；以及至少一个本地三级结构的元素。这些 特征，以及引人注目的保护 在十多株Delta毒株中进行了类病毒结构域测序，强度很大 建议此RNA结构域具有多种功能，包括 细胞蛋白质的结合部位。我们相信，许多 这个小RNA区域的功能--以及它经历结构变化的能力 变化--是相关的；控制从一个 另一种结构也可能控制生物功能。 我们的具体目标是：(一)进行详细的结构：功能 猪Delta类病毒核糖核酸结构域保守区的研究 以解释其结构特征与核酶作用的关系 和控制、细胞蛋白结合和功能RNA转换。 新发现的反式核酶反应将是这一努力的关键； (Ii)研究德尔塔的发病机制，以确定细胞组份。 蛋白质(例如来自SRP颗粒或细胞的RNA或蛋白质 抗病毒因素)，有时可以解释严重的症状 在三角洲肝炎中发现；以及(Iii)研究细胞成分和 参与Delta RNA复制的Delta RNA结构。

The viroids and viroid-like pathogens--and particularly the agent responsible for delta hepatitis--provide examples of RNA species heavily dependent on cellular components for their life cycles, creating potential imbalances in these components and cellular pathology. Several years ago we proposed a two-domain model for the 1700-base genomic RNA of the delta agent, in which the non-coding RNA was highly conserved and contained most or all of the functional domains needed for replication. This model has received wide support, and the non-coding domain has been named the "viroid-like" domain, which is now known to contain: RNA-cleaving ribozyme activities, which we have shown to contain a common motif and to be capable of trans cleavage; a region of homology with an abundant cellular RNA (the SRP RNA); two alternative secondary structures; and at least one element of local tertiary structure. These features, together with a remarkable conservation of a region of the viroid-like domain in more than ten delta strains sequenced, strongly suggest multiple functions for this RNA domain which could include binding sites for cellular proteins. We believe that many of the functions of this small RNA region--and its ability to undergo structural variation--are related; and that control of the transition from one structure to another may also control biological function. Our specific goals are (i) to carry out detailed structure:function studies on the conserved region of the delta viroid-like RNA domain in order to explain how its structural features relate to ribozyme action and control, cellular protein binding, and functional RNA transitions. The newly discovered trans ribozyme reactions will be key to this effort; (ii) to study delta pathogenesis in order to identify the cellular com- ponents (such as RNA or proteins from the SRP particles or cellular antiviral factors) which could explain the severe symptoms sometimes found in delta hepatitis; and (iii) to study cellular components and delta RNA structure involved in delta RNA replication.