RNA quality control and environmental stress

描述（由申请人提供）：该项目的长期目标是了解错误折叠的RNA如何在细胞内识别和处理，并研究RNA错误折叠如何影响细胞功能。我们的重点是Ro自身抗原，一种RNA结合蛋白，是系统性红斑狼疮患者免疫反应的主要靶点。在许多动物细胞的细胞质中，Ro结合称为Y RNA的小RNA。虽然Ro/Y RNA复合物的功能一直是谜，我们最近证明，Ro有2个保守的细胞功能。首先，Ro结合脊椎动物细胞核中错误折叠的缺陷小RNA，因此可能在小RNA质量控制中发挥作用。第二，Ro是哺乳动物细胞和至少一种真细菌在紫外线照射下存活的新途径的一部分。与在核损伤的识别或修复中的作用一致，Ro在照射后在核中积累。最令人惊讶的是，缺乏Ro的小鼠会患上类似于系统性红斑狼疮患者的自身免疫性疾病。这些研究结果表明，这种假定的RNA质量控制途径可能对保护细胞免受环境压力很重要，并提高了RNA质量控制失败可能导致疾病的可能性。我们的目标是达到一个机械的了解Ro功能，并揭示Y RNA在这些过程中发挥的作用。我们的第一个目标是确定Ro如何识别错误折叠的RNA，并研究Ro的结合是否针对它们进行降解。我们的第二个目标是阐明RO促进紫外线照射后哺乳动物和细菌细胞存活的机制。我们的第三个目标是研究Y RNA在小RNA质量控制和照射后细胞存活中的作用。由于Ro是唯一一种被描述为结合细胞中错误折叠的小RNA的蛋白质，因此对其功能的研究应该为研究很少但非常重要的生物过程提供见解。

DESCRIPTION (provided by applicant): The long term goals of this project are to understand how misfolded RNAs are recognized and handled within cells and to investigate how RNA misfolding impacts cell function. Our focus is on the Ro autoantigen, an RNA-binding protein that is a major target of the immune response in patients with systemic lupus erythematosus. In the cytoplasm of many animal cells, Ro binds small RNAs called Y RNAs. Although the function of the Ro/Y RNA complex has been enigmatic, we recently demonstrated that Ro has 2 conserved cellular functions. First, Ro binds misfolded, defective small RNAs in vertebrate cell nuclei, and thus likely plays a role in small RNA quality control. Second, Ro is part of a novel pathway by which mammalian cells and at least one eubacterium survive ultraviolet irradiation. Consistent with a role in the recognition or repair of nuclear damage, Ro accumulates in nuclei following irradiation. Most surprisingly, mice lacking Ro develop an autoimmune disease that resembles systemic lupus erythematosus in patients. These findings suggest that this putative RNA quality control pathway may be important for protecting cells from environmental stress and raise the possibility that failure of RNA quality control may result in disease. Our goal is to arrive at a mechanistic understanding of Ro function and to uncover the role that Y RNAs play in these processes. Our first aim is to determine how Ro recognizes misfolded RNAs and to investigate whether binding by Ro targets them for degradation. Our second aim is to elucidate the mechanism by which Ro facilitates mammalian and bacterial cell survival following ultraviolet irradiation. Our third aim is to examine the role of the Y RNAs in small RNA quality control and cell survival after irradiation. As Ro is the only protein described to bind misfolded small RNAs in cells, a study of its function should provide insights into a little-studied but highly important biological process.