EXOSC10-mediated pre-tRNA surveillance safeguards neuron survival

ABSTRACT tRNA quality control pathways have been identified in yeast, whereby aberrant and hypomodified mature tRNAs are targeted for 5’-3’ degradation by the rapid tRNA decay (RTD) pathway involving the Xrn1 and Rat1/Xrn2 exonucleases, whereas aberrant precursor tRNAs (pre-tRNAs) are targeted for 3’-5’ degradation by the nuclear surveillance pathway involving the RNA Exosome. However, the pathways controlling tRNA and pre-tRNA degradation in mammals have not yet been defined and the relevance of pre-tRNA surveillance pathways for normal cell physiology remains largely unknown. The RNA Exosome comprises a core of nine non-catalytic subunits (EXOSC1-9) to which the distinct, DIS3 and EXOSC10, 3’-5’ exonucleases associate. Here we find that EXOSC10 deficiency leads to accumulation of unspliced precursor tRNAs (pre-tRNAs) in mouse embryonic stem cells (ESCs) and is required for pre-tRNA decay in biochemical assays. Pre-tRNA overexpression causes diminished motor neuronal survival in a mouse ESC differentiation model. Our results identify a pre-tRNA decay pathway that links Exosome deficiency with neuron survival and provides insight into possible pathological mechanisms underlying human neurodevelopmental disorders caused by mutations in Exosome subunits and genes involved in tRNA biogenesis. Exosc10 is required for pre-tRNA surveillance in cells and degradation in biochemical assays Pre-tRNA expression inhibits survival of neurons Pre-tRNA decay pathway links exosome deficiency with neurodevelopmental disorders