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

• Applicant: Dr. Sibylle Mitschka
• Subject Area: Cell Biology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 362707874

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Dr. Christine Mayr