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

mRNA命运的调控本质上是由mRNA结合蛋白（mrbp）和反式非编码rna（包括microRNAs和lncRNAs）的相互作用控制的。在细胞质中，mRNA翻译和周转的调控主要是通过mRNA特异性mrbp组件组成的mRNA来调控的。在最近的研究中，我们发现各种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位点体（histone locus bodies, HLBs）的传递，从而促进复制依赖性组蛋白前mRNA的3端加工。组蛋白位点体是组蛋白mRNA合成和3端加工的部位。与Y3**不同，Y1和Y3主要是细胞质。这两种Y rna都与Y RNPs中的各种mrbp结合，其中mrbp主要通过Y rna的单链环结合，Ro60在茎部结合，La通过Y rna 3端富含polyu的延伸结合。我们认为Y RNPs是mRNP组装的重要调节剂，控制着mrbp的亚细胞分选、它们的周转、翻译后修饰和/或复合物的形成。因此，Y RNPs有望调节mrna的细胞质命运，从而通过支架、隔离和/或陪伴mrbp来调节基因表达的转录后控制。本研究旨在通过以下几个方面来解读Y RNA蛋白调控mRNP/mRBP功能的分子机制：1)Y RNA蛋白相互作用组的表征和验证；2) Y rna在mrbp的mrnp关联调控中的作用；3) Y rna在调节mrbp亚细胞分选中的作用；4) Y rna在mRBP蛋白转换和修饰中的作用；5) Y rna在mrbp导向的细胞质mRNA命运控制中的作用。我们期望所提出的研究将揭示mRBP/mRNP功能调控的重要见解，特别是在癌症来源的细胞中。在后者中，已报道了Y rna，特别是Y1和Y3以及几种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。

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.