A reduction in tRNA ligation results in the accumulation of tRNA half fragments, which inhibit protein translation and cause cell death in yeast and mammalian cells (Sobala and Hutvagner, 2013; Thompson et al., 2008; Thompson and Parker, 2009; Yamasaki et al., 2009). The CLP1 kinase-dead mice accumulated a 5’-tRNA exon derivative fragment, but we found no evidence of accumulation or toxicity of this fragment in human cells. Instead, we found that unphosphorylated 3’-exon (i.e. a substrate for CLP1) but not the phosphorylated 3’-exon exacerbated toxicity. Our findings support a required role for CLP1 in the 5’-end phosphorylation-dependent ligation of “half”-tRNAs in humans. Cumulatively, we uncover a cell-type specific requirement for the HSPC117-independent tRNA maturation pathway in human development, which when perturbed causes a new PCH-like neurological disease.
