Mammalian Polycistronic mRNAs and Disease

Abstract

Our understanding of gene expression has come far since the “one-gene one-polypeptide” hypothesis proposed by Beadle and Tatum. This review addresses the gradual recognition that a growing number of polycistronic genes, originally discovered in viruses, are being identified within the mammalian genome, and that these may provide new insights into disease mechanisms and treatment. We have carried out a systematic literature review identifying 13 mammalian genes for which there is evidence for polycistronic expression via translation through an Internal Ribosome Entry Site (IRES). Although the canonical mechanism of translation initiation has been studied extensively, this review highlights a process of non-canonical translation, IRES-mediated translation, that is a growing source of understanding complex inheritance, elucidation of disease mechanisms, and discovery of novel therapeutic targets. Identification of additional polycistronic genes may provide new insights into disease therapy and allow for new discoveries of translational and disease mechanisms.

Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship

“…These ORFs are at the same locus as an annotated CDS but encoded in an alternative reading frame and can either partially overlap the CDS or be completely nested within it. Several mammalian polycistronic mRNAs have been reported over the past decade (for review, see Karginov et al 2017). These overlapping ORFs might be more common than previously thought, given that 30% of peptides from Slavoff's study were mapped back to overlapping ORFs (Slavoff et al 2013).…”

“…These detection methods-ribosome profiling, proteogenomics, and conservation signatures-are revealing this hidden proteome, a novel repertoire for biomarkers and therapeutic strategies (Couso and Patraquim 2017;Karginov et al 2017;Plaza et al 2017). Here, we briefly review functional evidence for the biological roles of alternative proteins.…”

Tissue and regional expression patterns of dicistronic tRNA-mRNA transcripts in grapevine (Vitis vinifera) and their evolutionary co-appearance with vasculature in land plants

“…Polycistronic mRNAs are RNA molecules that contain two or more open reading frames (ORFs). These are usually found in viruses, bacteria, archaea, protozoans and invertebrates (Karginov et al 2017). Polycistronic transcripts are synthesized when multiple genes forming an operon are coexpressed from a single promoter.…”

“…These transcripts are then translated into protein from two or more translation initiation sites. This strategy has been described as an efficient mechanism to coordinate gene expression (Karginov et al 2017). Although polycistronic transcripts are less common in plants, several chloroplast genes are organized in clusters and are co-transcribed in polycistronic primary transcripts and subsequently processed to form mature RNAs (Sugita and Sugiura 1996), reflecting their prokaryotic ancestry (Barkan 2011).…”

A New Way to Discover IRESs in Pathology or Stress Conditions? Harnessing Latest High‐Throughput Technologies

“…As a result, only a small number of IRES elements have been identified using the method. Furthermore, for this assay, additional experiments should be performed to exclude the possibility of cryptic promoter activity or mRNA splicing, because the increased expression of the second cistron may also be caused by these events . Although a high‐throughput method based on next generation sequencing (NGS) was developed recently, it aimed to identify IRES elements from synthetic DNA fragments .…”