Kevin Van Bortle

The RNA polymerase III (Pol III) transcriptome is universally comprised of short, highly structured noncoding RNA (ncRNA). Through RNA–protein interactions, the Pol III transcriptome actuates functional activities ranging from nuclear gene regulation (7SK), splicing (U6, U6atac), and RNA maturation and stability (RMRP, RPPH1, Y RNA), to cytoplasmic protein targeting (7SL) and translation (tRNA, 5S rRNA). In higher eukaryotes, the Pol III transcriptome has expanded to include additional, recently evolved ncRNA species that effectively broaden the footprint of Pol III transcription to additional cellular activities. Newly evolved ncRNAs function as riboregulators of autophagy (vault), immune signaling cascades (nc886), and translation (Alu, BC200, snaR). Notably, upregulation of Pol III transcription is frequently observed in cancer, and multiple ncRNA species are linked to both cancer progression and poor survival outcomes among cancer patients. In this review, we outline the basic features and functions of the Pol III transcriptome, and the evidence for dysregulation and dysfunction for each ncRNA in cancer. When taken together, recurrent patterns emerge, ranging from shared functional motifs that include molecular scaffolding and protein sequestration, overlapping protein interactions, and immunostimulatory activities, to the biogenesis of analogous small RNA fragments and noncanonical miRNAs, augmenting the function of the Pol III transcriptome and further broadening its role in cancer. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Processing of Small RNAs RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications