Mitonuclear control of transcription complexes regulates tRNA splicing

The human genome has hundreds of tRNA genes, a subset of which is intervened by short introns. Transcription of the latter genes by RNA polymerase (Pol) III generates precursor tRNAs that undergo splicing by the tRNA splicing complex, in addition to the removal of flanking sequences by RNase P and RNase Z. The former enzyme consists of tRNA splicing endoribonuclease complex and tRNA ligase complex. However, it was unknown how and where the human tRNA splicing complex executes its function in cells. We show that transcription complexes assembled on intron-containing tRNA genes possess a tRNA ligase complex and that this enzyme is regulated by a mitonuclear communication mechanism. A cytoplasmic, mitochondria-associated HSPC117, the catalytic subunit of the tRNA ligase complex, transiently relocates to the nucleoplasm in the S phase of the cell cycle to promote the second step of splicing, exon ligation, of select tRNAs. This nuclear localized RTCB-type ligase acts as an integral part of transcription complexes. Knockout of HSPC117 or expression of an inactive mutant of this enzyme leads to severe inhibition of transcription and exon ligation due to the assembly of deficient transcription complexes. Inhibition also brings to deficiency of the perinucleolar compartments, as a result of reduced expression of the H1 RNA essential to Pol III transcription in cells. This study demonstrates that transcription complexes execute splicing of select intron-containing tRNAs and that this two-stage reaction is time-based on a mitonuclear communication mechanism that controls the tRNA ligase HSPC117 in human cells.