Functions of many long noncoding RNAs (lncRNAs) depend on their ability to interact with multiple copies of specific RNA-binding proteins (RBPs). Here, we devised a workflow combining bioinformatics and experimental validation steps to systematically identify RNAs capable of multivalent RBP recruitment. This uncovered a number of previously unknown transcripts encoding high-density RBP recognition arrays within genetically normal short tandem repeats. We show that a top-scoring hit in this screen, lncRNA PNCTR, contains hundreds of pyrimidine tract-binding protein (PTBP1)-specific motifs allowing it to sequester a substantial fraction of PTBP1 in a nuclear body called perinucleolar compartment. Importantly, PNCTR is markedly overexpressed in a variety of cancer cells and its downregulation is sufficient to induce programmed cell death at least in part by stimulating PTBP1 splicing regulation activity. This work expands our understanding of the repeat-containing fraction of the human genome and illuminates a novel mechanism driving malignant transformation of cancer cells.
Human genome encodes many transcripts enriched in short tandem repeats (strRNAs)
strRNA PNCTR recruits RNA-binding protein PTBP1 to a nuclear body called PNC
PNCTR antagonizes splicing regulation function of PTBP1 and promotes cell survival
PNCTR is dramatically upregulated in a wide range of cancer cells
Yap et al. show that several short tandem repeats (STRs) encoded in the human genome are transcribed at a readily detectable level. The STR-enriched RNA PNCTR sequesters multiple copies of PTBP1 in the perinucleolar compartment, thus modulating splicing regulation function of this RNA-binding protein and promoting cancer cell survival.