NSF-BSF: Circular RNAs as a Primate-specific Mechanism to Create Proteome Diversity: Participant Scope

A central biological question in human biology is: How can matter be organized into a self- aware brain? During evolution, cognitive brain functions increased in the primate lineage, peaking in humans and other great apes. This increase in primate brain function correlates with the expansion of Alu-elements that make up 10.7% of the human genome, but the molecular reason for this correlation is unknown. Circular RNAs are a new class of covalently linked RNA circles that are generated through backsplicing, where a 5’ splice site is connected to an upstream 3’ splice site. Back-splicing is promoted by pre-mRNA structures, which in turn are generated through base complementarities between Alu- elements. We found that adenosine to inosine RNA editing strongly promotes translation of circular RNAs, which compensates for the lack of a 5’ cap structure and known ribosomal entry sites. Translation of circular RNAs occurs in rolling circles, resulting in multimers of parts of ‘linear’ proteins or in novel proteins if frameshifts occur. We will test the hypothesis that Alu-elements promote the formation of primate-specific circular RNAs that are translated into proteins after undergoing epigenetic adenosine to inosine RNA editing. Thus, by promoting circular RNAs, Alu-elements generated a primate-specific ‘circular proteome’ that strongly increased molecular complexity in the brain, which could enhance brain functions. We will test our hypothesis by #1 determining the molecular mechanism of inosine-dependent circRNA translation, #2 by determining the factors that control the balance between linear and circular RNA splicing in the presence of Alu-elements and #3 by analyzing the molecular function of candidate circProteins at hand. Testing our highly novel hypothesis could unveil a so far unknown circular proteome that could be a crucial element in human brain function. To raise awareness for the underappreciated role of RNA in biology, we will train US and Israeli students in three RNA summer schools at Hebrew University, using wet-lab experiments and 12 theoretical lectures made available on YouTube, on both graduate and high-school student level. Theoretical questions of this course will be published as a book: RNA-a practical approach.