THREE STOP CODONS TO GET OVER TO FLOURISH

forthcoming

An accumulating body of evidence reveals that the Genetic Code, canonically interpreted in codons of three nucleotides, is not universal. In dogma challenging findings, we have observed in unicellular protists a remarkable malleability of genetic decoding that is mostly governed by tRNAs that interpret codons as having different meanings depending on their location in the genome. For example, coding sequences of our model protist Blastocrithidia nonstop are rich in stop codons and unique tRNA architectures are employed to readthrough them efficiently. Importantly, these internal stops very much resemble premature termination codons (PTC) in humans that lead to truncated proteins and are the cause of ~11% of human genetic disease. As such, these small RNA molecules with innate readthrough properties hold tremendous promise for the treatment of disease. Our first objective is to explore and characterize the molecular mechanisms of alternative genetic decoding in protists where this phenomenon is most prominent. Armed with this knowledge, our second objective is to engineer tRNAs and tRNA-specific readthrough-inducing drugs (TRIDs) for programmable alterations of genetic decoding in heterologous systems. tRNAs and TRID will then be applied in cellular and animal models of severe monogenic paediatric diseases. We have assembled a team that synergizes expertise across disciplines. JL is a leading protist biologist, LV specializes on translational control, ON in engineering stop codon readthrough drugs, and MO in clinical disease models. This intertwined collaboration of all four PIs will expedite the characterization of alternative decoding mechanisms and their ultimate application in cellular and in vivo models of human diseases. Successful completion of 3Stops2Go is only possible by close teamwork and aims to deliver a new class of tRNA molecules and readthrough pharmaceuticals that will be a paradigm shift in basic science with direct and broad therapeutic potential.