Evolutionary conservation of protein functions accomplished by 3’UTR-mediated protein-protein interactions

全基因组转录终止图谱显示，大约一半的人类蛋白质编码基因通过一种称为选择性切割和多腺苷基化(APA)的机制产生可选的转录本。这种机制导致转录组的种类和复杂性大大增加。在大多数情况下，这些可供选择的mRNA变体的生物学作用仍不清楚，它们只在3‘非翻译区(3’UTR)上存在差异。到目前为止，研究主要集中在这些转录本在mRNA稳定性和翻译效率方面受到差异调控的可能性，例如通过miRNA介导的过程。然而，Berkovits和Mayr最近发表的一项研究(自然，2015)可能表明，3‘UTRs可以作为RNA结合蛋白质的对接位点，从而介导特定的蛋白质与翻译位点上已经存在的新生蛋白质链的相互作用。具体地说，研究表明，CD47基因的长非编码区变体负责产生一池蛋白质，该蛋白质池更有效地运输到质膜。相反，短3‘非编码区变体的蛋白质主要保留在细胞内，并发挥抗细胞凋亡的功能。这种新的机制显然不依赖于不同的mRNA定位，并可能在多种蛋白质中发挥重要作用。基于这些发现，我的研究员计划的目的是进一步研究替代的3‘UTR转录表达在蛋白质功能调节中的影响。为此，我想分析四个候选基因(RAC1、GSK3B、PTEN和YAP1)的蛋白质相互作用组，以了解一个基因的长和短3‘UTR转录本产生的蛋白质的特定相互作用因子之间的差异。通过比较所研究基因的人和鸡的同源基因，我想回答的问题是，作为一种调节蛋白质功能的手段，3‘UTR介导的蛋白质招募在进化过程中保守了多少。此外，我还有兴趣在分子水平上阐明3‘UTR介导的蛋白质相互作用的特异性调节机制。这四个候选基因在mRNA的编码区和非编码区都高度保守，由于它们与不同的人类疾病有关，因此具有很高的医学意义。因此，进一步了解调节其功能的机制是特别有意义的。总之，我相信这项研究将为3‘UTRs在蛋白质功能调控中的作用提供有价值的见解。

Genome-wide mapping of transcript termination has revealed that about half of all human protein-coding genes produce alternative transcripts through a mechanism called alternative cleavage and polyadenylation (APA). This mechanisms leads to a substantial increase in the variety and complexity of the transcriptome. The biological role of these alternative mRNA variants, which in most cases only differ in their 3'untranslated region (3'UTR) is still not sufficiently understood. So far, research has mainly focused on the potential of these transcripts to be differentially regulated regarding mRNA stability and translational efficiency, for instance through miRNA-mediated processes. However, a recently published study by Berkovits and Mayr (Nature, 2015) could show that 3'UTRs can serve as docking sites for RNA-binding proteins which in turn mediate specific protein interactions with the nascent protein chain already at the site of translation. Specifically, it was shown that the long UTR variant of the gene CD47 is responsible for generating a pool of protein that is more efficiently transported to the plasma membrane. In contrast, protein of the short 3'UTR variant remains mostly intracellularly and fulfills anti-apoptotic functions. This new mechanism does explicitly not rely on differential mRNA localization and could potentially play an important role for a variety of proteins.Building on these findings, the aim of my fellowship proposal is to further investigate the impact of alternative 3'UTR transcript expression in the regulation of protein function. For this purpose, I want to analyze the protein interactome of four candidate genes (RAC1, GSK3B, PTEN and YAP1) with regards to differences between specific interactors of proteins generated from long and short 3'UTR transcripts of a gene. By comparing the human and chicken homologs of the investigated genes, I would like to answer the question in how far 3'UTR-mediated protein recruitment as a means to regulate protein function is conserved during evolution. Furthermore, I am also interested in elucidating the mechanisms that regulate the specificity of 3'UTR-mediated protein interactions at the molecular level. The four selected candidate genes are highly conserved in both the coding as well as the non-coding regions of the mRNA and have a high medical relevance due to their implication in different human disease. To further the understanding of the mechanisms which are responsible for the modulation of their function is therefore of particular interest. In summary, I believe that this study will offer valuable insights into the role of 3'UTRs in the regulation of protein functions.