The role of NSUN2 in tRNA derived small RNA biogenesis and nascent RNA silencing

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All organisms consist of cells that multiply through cell division. The genetic code, which defines each cell type, is storedwithin DNA molecules. DNA contains coding regions called genes. Genes are transcribed into messenger RNA (mRNA)molecules, which are in turn translated into proteins, a process called gene expression. It is important that each cell makesthe right levels of proteins, which is achieved by controlled gene expression. Uncontrolled gene expression can lead tocancer or cell death. One of the most important mechanisms for the regulation of gene expression is gene silencing. Genesilencing in human cells requires the presence of small RNA molecules (siRNA) that lead to recognition and destruction oftarget mRNA in the cytoplasm. Another type of gene silencing is the establishment of specific modifications on DNA, whichleads to inhibition of gene transcription, also called transcriptional gene silencing (TGS).Pathway that leads to gene silencing is called RNA interference (RNAi) and this great discovery was recognised by Nobelprize in 2006. RNAi was widely explored not only as an important scientific tool, but also as novel therapeutic agent. Withvery first FDA approved drug, Patisiran, sRNA-based therapeutics are now receiving more and more attention.We have discovered novel gene silencing pathway that is very distinct from well-known PTGS or TGS. We found that tRNAmolecules that are essential for protein production, can fold into various alternative shapes. Such non-canonical structuresare recognised by Dicer, enzyme that can cleave them into tRNA-derived small RNA molecules, called tsRNAs. tsRNAsare not just degradation products of misfolded tRNAs, but they are functional and suppress expression of many diseasedriving genes. It is very important to understand how is the balance between proper tRNA structures (clover leaf) andalternative structures regulated. We propose that modifying enzyme, NSUN2, can determine the foldingabilities of tRNAs and consequently their recognition and cleavage by Dicer. Furthermore, we hypothesise thatmodifications on tsRNAs can have direct impact on efficiency of nascent RNA silencing. This proposal has directtranslational potential in identifying key features of novel tsRNA-based therapeutics.