Mechanism and Regulation of mRNA Export

mRNA输出的机制和调控

• 批准号: 7289904
• 负责人: RAVI DHAR
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7289904
• 关键词: Mechanism; Regulation; mRNA; Export

The nuclear export of mRNA is a multistep process mediated by mRNA-export protein complexes (mRNP). The formation of these complexes takes place concurrently and in coordination with the steps involved in mRNA formation, starting from the synthesis of nascent pre-mRNA molecule, through its splicing and subsequent processing steps. One such step is the recruitment of export factors, directly or via other mediators, onto the mRNA molecule during or after transcription. A second critical step is the targetting of the mRNP complex to the nuclear pore, which is composed of large multi-protein structures called the nuclear pore complex (NPC). Following targeting, the translocation of the mRNP complexes is thought to occur through the NPC by repeated interaction between mRNPs and the hydrophobic phenylalanine glycine (-FG) patches on the pore associated proteins lining the wall of the tubular pore channel. At the cytoplamic side the mRNPs are released. Our studies where designed to define these different steps of mRNA export, and identify the protein-protein interaction that is required for progression of the mRNP-complexes through various steps of the mRNA export proves.The breast cancer tumor suppressor BRCA-2 interacting protein, DSS1, and its homolog are critical for DNA recombination in eukaryotic cells. We found that Dss1p, along with Mlo3p and Uap56p, Schizosaccharmyces pombe (S. pombe) homologs of two mRNAs export factorsa of the NXF-NXT pathway, is required for mRNA export in S. pombe. Previously we showed that the nuclear pore-associated Rae1p is an essential mRNA export factor in S. pombe. We have shown that Dss1p and Uap56p function by linking mRNA export adaptor Mlo3p to Rae1p for targeting mRNA-protein (mRNP) complex to the proteins of the nuclear pore complex. Dss1p preferentially recruits to genes in vivo and interacts with -FG (phenylalanine glycine) nucleoporins in vivo and in vitro. Thus, Dss1p may function at multiple steps of mRNA export, from mRNP biogenesis to targeting and translocation through the NPC.

mRNA的核输出是由mRNA-Export蛋白复合物（MRNP）介导的多步过程。这些复合物的形成是同时进行的，并与MRNA形成所涉及的步骤进行协调，从新生的前MRNA分子的合成开始，其剪接和随后的处理步骤。这样的步骤之一是在转录期间或之后，直接或通过其他介体通过其他介体募集出口因子到mRNA分子上。第二个关键步骤是将MRNP复合物靶向核孔，该核孔由称为核孔复合物（NPC）的大型多蛋白结构组成。靶向后，认为MRNP复合物的易位通过NPC通过MRNPS与孔相关蛋白上的疏水性苯丙氨酸甘氨酸（-FG）斑块之间的反复相互作用而发生。在细胞环侧，mRNP被释放。我们的研究旨在定义mRNA输出的这些不同步骤，并确定通过mRNA输出的各个步骤进展的蛋白质蛋白质相互作用，这证明了MRNP-复合体的进展。我们发现，DSS1P以及MLO3P和UAP56P，schizosaccharmyces pombe（S。pombe）同源物的NXF-NXT途径的两个mRNA ExportAFARTA，S。POMBE中需要MRNA Export。以前我们表明，与核孔相关的RAE1P是S. pombe中必不可少的mRNA输出因子。我们已经表明，DSS1P和UAP56P通过将mRNA导出适配器MLO3P与RAE1P连接到靶向mRNA-蛋白（MRNP）复合物与核孔复合物的蛋白质的功能。 DSS1P优先募集体内基因，并与-fg（苯丙氨酸甘氨酸）核孔蛋白在体内和体外相互作用。因此，从mRNP生物发生到通过NPC靶向和易位，DSS1P可能在mRNA输出的多个步骤中起作用。