Classical genes encoding proteins have been long known to occupy only a small part of the human genome with possible functions of the remaining DNA being largely enigmatic. Recent evidence suggests that many of these DNA sequences can give rise to long noncoding RNAs (lncRNA), extensive transcripts that are not translated into proteins. According to some calculations the number of lncRNAs in our genome may exceed the number of protein-coding genes. Yet, we know surprisingly little about biological significance of this abundant class of RNA molecules.
Researchers from the Centre for Developmental Neurobiology, King’s College London have just published a collaborative study that identifies a new group of lncRNAs containing so-called short tandem repeats (STRs), multiple iterations of 2-12 nucleotide-long “words”. Detailed analysis of one such transcript, PNCTR, expressed at relatively high levels in a variety of cancer cells, showed that it contributes to regulation of alternative splicing and is critical for cell survival. This can be explained, at least in part, by the presence of hundreds of specific motifs in the PNCTR sequence allowing this lncRNA to sequester multiple copies of an important RNA-binding protein, PTBP1. Interestingly, PTBP1 sequestration occurs in a specialized spot inside the nucleus called the perinucleolar compartment, and PNCTR is absolutely essential for the integrity of this cancer-enriched nuclear body.
All in all, this work sheds new light on biological activities of lncRNAs and uncovers a novel mechanism that promotes malignant transformation of cancer cells.
PNCTR and several other STR-containing lncRNAs are clearly overexpressed in transformed cells and it will be interesting to explore possible use of these molecules in tumour diagnostics and treatment.
We are really excited about this work since it suggests that the part of our genome that has been traditionally thought to be meaningless can in fact have important cellular functions
Eugene Makeyev, corresponding author.
This work was supported by the Biotechnology and Biological Sciences Research Council (BB/M007103/1 and BB/R001049/1), European Commission (H2020-MSCA-RISE-2016; Project ID 734791), and the National Medical Research Council (NMRC/CBRG/0028/2013).