TRNAU1AP and PRPF39 establish integrated control over processing of most abundant human non-coding RNAs

Although abundance of the metastasis-associated long non-coding RNA MALAT1 depends on the maturation of its triple-helix-containing 3' end via non-canonical processing, the control of this step has remained unknown. Using iterative genome-wide screening, we identified TRNAU1AP and PRPF39 that together control the 3'-end processing of MALAT1, enabling a reduction in its levels. We further show that these factors form part of a previously unrecognized RNase MRP and P control (RMPPc) pathway that, in addition to MALAT1, establishes integrated control over the processing of MEN-β, internal transcribed spacers in pre-rRNA, and 5'-leader sequences in pre-tRNA, thereby impacting fundamental processes prerequisite for translation. We demonstrate that this far-reaching impact is achieved through a single control point: inclusion of the initiating ATG-containing exon 2 in RPP14, an essential component of both RNase MRP and RNase P, thereby controlling both catalytic RNAs-MRP RNA and H1 RNA. Finally, we show that upstream of this primary control point, the RMPPc pathway forms a remarkably interlinked four-pronged feedback circuit that confers stability on post-transcriptional processing of over 90% of the total RNA content in human cells.