Control of mRNA-binding protein (mRBP) and mRNP function by Y RNAs

Y RNA 控制 mRNA 结合蛋白 (mRBP) 和 mRNP 功能

• 批准号: 313603706
• 负责人: Professor Dr. Stefan Hüttelmaier
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/313603706?language=en
• 关键词: Control; mRNA; binding; protein; mRBP

The regulation of mRNA fate is essentially controlled by the interplay of mRNA-binding proteins (mRBPs) and trans-acting noncoding RNAs including microRNAs and lncRNAs (long noncoding RNAs). In the cytoplasm, the regulation of mRNA translation and turnover is largely regulated via mRNPs comprising mRNA-specific mRBP-assemblies. In recent studies, we identified that various mRBPs associate with noncoding Y RNAs. The Y3** promotes the 3-end processing of replication dependent histone pre-mRNA by modulating the assembly of CPSF-associated complexes and their delivery to histone locus bodies (HLBs), the site of histone mRNA synthesis and 3-end processing. In contrast to Y3**, Y1 as well as Y3 are mainly cytoplasmic. Both Y RNAs associate with various mRBPs in Y RNPs comprising mRBPs largely associating via the single-stranded loop of Y RNAs, Ro60 binding at the stem and La associating via a polyU-rich stretch at Y RNAs 3-end. We propose that Y RNPs are essential modulators of mRNP assembly controlling the subcellular sorting of mRBPs, their turnover, post-translational modification and/or complex formation. Accordingly, Y RNPs are expected to modulate the cytoplasmic fate of mRNAs and thus the post-transcriptional control of gene expression by scaffolding, sequestering and/or chaperoning mRBPs. This proposal aims at deciphering the molecular mechanisms underlying Y RNP-directed regulation of mRNP/mRBP function by focusing on the following aspects: 1) Characterization and validation of the Y RNA protein-interactome; 2) The role of Y RNAs in modulating the mRNP-association of mRBPs; 3) The role of Y RNAs in modulating subcellular sorting of mRBPs; 4) The role of Y RNAs in modulating mRBP protein turnover and modification; 5) The role of Y RNAs in controlling mRBP-directed control of cytoplasmic mRNA fate. We expect that the proposed studies will reveal important insights into the regulation of mRBP/mRNP function, in particular in cancer-derived cells. In the latter, upregulated expression of Y RNAs, in particular Y1 and Y3 along with several mRBPs has been reported. Accordingly, the proposed studies will set the stage for evaluating the role of Y RNA-controlled mRBP/mRNP function in cancer.

mRNA命运的调节基本上由mRNA结合蛋白（mRBP）和反式作用非编码RNA（包括microRNA和lncRNA（长非编码RNA））的相互作用控制。在细胞质中，mRNA翻译和周转的调节主要通过包含mRNA特异性mRBP组装体的mRNP来调节。在最近的研究中，我们确定了各种mRBP与非编码Y RNA相关。Y3** 通过调节CPSF相关复合物的组装及其向组蛋白基因座体（HLB）（组蛋白mRNA合成和3-末端加工的位点）的递送来促进复制依赖性组蛋白前mRNA的3-末端加工。与Y3** 相反，Y1以及Y3主要是细胞质的。两种Y RNA都与Y RNP中的各种mRBP缔合，所述Y RNP包含主要经由Y RNA的单链环缔合的mRBP、在茎处结合的Ro 60和经由Y RNA 3-末端处的富含polyU的延伸缔合的La。我们认为Y RNP是控制mRNP亚细胞分选、周转、翻译后修饰和/或复合物形成的mRNP组装的重要调节剂。因此，预期Y RNP调节mRNA的细胞质命运，并因此通过支架、隔离和/或陪伴mRBP调节基因表达的转录后控制。本研究的目的是通过以下几个方面来阐明Y RNA介导的mRNP/mRBP功能调控的分子机制：1）Y RNA蛋白相互作用组的表征和验证; 2）Y RNA在调节mRNP/mRBP的mRNP-缔合中的作用; 3）Y RNA在调节mRBP的亚细胞分选中的作用; 4）Y RNA在调节mRBP蛋白周转和修饰中的作用; 5）Y RNA在控制mRBP指导的细胞质mRNA命运控制中的作用。我们希望这些研究将揭示mRBP/mRNP功能调控的重要见解，特别是在癌症衍生细胞中。在后者中，已经报道了Y RNA，特别是Y1和Y3沿着几种mRBP的上调表达。因此，拟议的研究将为评估Y RNA控制的mRBP/mRNP功能在癌症中的作用奠定基础。