Coordination of Processing and Transport of mRNA

mRNA 加工和运输的协调

• 批准号: 6887312
• 负责人: Pamela A Silver
• 金额: $ 42.84万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6887312
• 关键词: RNA binding protein; enzyme activity; enzyme inhibitors; heterogeneous nuclear ribonucleoprotein; immunoprecipitation; intracellular transport; messenger RNA; methylation; methyltransferase; microarray technology; nuclear membrane; nuclear transfer; nuclear transport; peptide library; polymerase chain reaction; posttranscriptional RNA processing; tissue /cell culture; RNA binding protein; enzyme activity; enzyme inhibitors; heterogeneous nuclear ribonucleoprotein; immunoprecipitation; intracellular transport; messenger RNA; methylation; methyltransferase; microarray technology; nuclear membrane; nuclear transfer; nuclear transport; peptide library; polymerase chain reaction; posttranscriptional RNA processing; tissue /cell culture

The long-term objective of the proposed research is to understand the mechanism by which mRNAs are exported out of the nucleus. The process of mRNA export includes: proper processing, packaging into protein-RNA complexes, targeting to and movement through the nuclear pore complex and release into the cytoplasm for translation. A transport machinery distinct from that for protein export has been proposed for mRNAs. As with protein import and export, mRNA export can also be regulated by, for example, growth conditions and viral infection. The Specific Aims are to determine how: 1) mRNAs are co- transcriptionally recruited for export; 2) mRNAs are recognized in the nucleus by certain RNA binding proteins; 3) mRNAs are selectively exported under conditions of stress; and 4) protein methylation of RNA binding proteins at arginine affects their activity. Defects in mRNA metabolism that can affect transport are associated with a number of diseases thus contributing to the health-relatedness of the project. For example, splicing and 3' end formation are associated with a number of diseases including metastatic cancers, muscular dystrophy and amyotrophic lateral sclerosis. In addition, some viruses exploit the endogenous nuclear transport machinery in order to propagate - in some cases by inhibiting export of host in favor of viral messages. Methylation of RNA and DNA binding proteins at arginine has recently emerged as important for many levels of regulation including viral RNA export, response of cells to interferon and the action of certain RNA binding proteins in motor neuron degeneration in spinal muscular atrophy. Lastly, arginine-methylated proteins such as hnRNPs and myelin basic protein are prominent in autoimmune diseases such as systemic lupus erythematosus and multiple sclerosis. It may be that modified arginine elicits special recognition properties that lead to exacerbation of autoimmune diseases.

拟议研究的长期目标是了解将mRNA从细胞核中导出的机制。 mRNA输出的过程包括：适当的加工，包装到蛋白质-RNA复合物中，靶向和通过核孔复合物运动并释放到细胞质中进行翻译。 已经提出了一种与蛋白质导出不同的运输机制。 与蛋白质进口和出口一样，mRNA输出也可以受到例如生长条件和病毒感染的调节。具体目的是确定：1​​）MRNA是在转录上招募出口的； 2）在细胞核中通过某些RNA结合蛋白识别mRNA； 3）在压力条件下，mRNA被选择性地出口； 4）精氨酸的RNA结合蛋白的蛋白甲基化会影响其活性。可能影响运输的mRNA代谢缺陷与多种疾病有关，从而导致该项目的健康相关性。 例如，剪接和3'端形成与多种疾病有关，包括转移性癌症，肌肉营养不良和肌萎缩性侧面硬化症。 此外，某些病毒利用内源性核运输机制来传播 - 在某些情况下，通过抑制宿主出口而有利于病毒信息。 对于许多水平的调节，包括病毒RNA输出，细胞对干扰素的反应以及在脊柱肌肉萎缩中运动神经元变性中某些RNA结合蛋白的作用，RNA和DNA结合蛋白在精氨酸上的甲基化最近出现了。 最后，精氨酸 - 甲基化蛋白（例如HNRNP和髓磷脂碱性蛋白）在自身免疫性疾病中很明显，例如全身性红斑狼疮和多发性硬化症。修饰的精氨酸可能引起特殊识别特性，从而导致自身免疫性疾病加剧。