In this study, we focus on the role of CLP1 in tRNA processing and show elevated levels of some unspliced pre-tRNAs and depletion of some mature tRNAs for several different isoacceptors including Tyrosine, Isoleucine and Leucine in iNeurons. This result implies reduced processivity of pre-tRNAs to mature tRNAs when CLP1 is mutated, which we predict occurs at both the pre-tRNA cleavage step and the ligation step directly downstream of CLP1 in the processing cascade. The presence of the HSPC117 redundant splicing pathway may account for the rescue of processed tRNA levels in the presence of the CLP1 mutation in fibroblasts, although we found no phenotype upon hspc117 knockdown in fish, and no genetic interaction with clp1. Thus the relative contributions of the two tRNA splicing pathways, or others yet undefined, will require further investigation.
