Abstract
mRNAs carry the genetic information that is translated by ribosomes. The traditional view of a mature eukaryotic mRNA is a molecule with three main regions, the 5′ UTR, the protein coding open reading frame (ORF) or coding sequence (CDS), and the 3′ UTR. This concept assumes that ribosomes translate one ORF only, generally the longest one, and produce one protein. As a result, in the early days of genomics and bioinformatics, one CDS was associated with each protein-coding gene. This fundamental concept of a single CDS is being challenged by increasing experimental evidence indicating that annotated proteins are not the only proteins translated from mRNAs. In particular, mass spectrometry (MS)-based proteomics and ribosome profiling have detected productive translation of alternative open reading frames. In several cases, the alternative and annotated proteins interact. Thus, the expression of two or more proteins translated from the same mRNA may offer a mechanism to ensure the co-expression of proteins which have functional interactions. Translational mechanisms already described in eukaryotic cells indicate that the cellular machinery is able to translate different CDSs from a single viral or cellular mRNA. In addition to summarizing data showing that the protein coding potential of eukaryotic mRNAs has been underestimated, this review aims to challenge the single translated CDS dogma.
Highlights
The general vision of a typical eukaryotic mature mRNA is a monocistronic molecule with a tripartite structure: a single translated open reading frame (ORF) or coding sequence (CDS) is flanked by 5 and 3 UTRs (Figure 1A)
Bicistronic mRNAs were detected in plants and some aspects of the translational mechanisms for these mRNAs have been elucidated [1], this review will mainly focus on animal mRNAs
Similar to mRNAs, long noncoding RNAs (lncRNAs) may be an important source of alternative ORFs (altORFs), but this review focuses on currently annotated proteincoding transcripts or mRNAs
Summary
The general vision of a typical eukaryotic mature mRNA is a monocistronic molecule with a tripartite structure: a single translated ORF or CDS is flanked by 5 and 3 UTRs (Figure 1A). In contrast to bacterial ribosomes which can bind to internal binding sites in polycistronic mRNAs, the cap-dependent scanning mechanism as currently visioned is not compatible with the translation of several CDSs in the same mRNA molecule. It was concluded well before the pre-genomic era that each mature eukaryotic mRNA is monocistronic and is translated into a single polypeptide [5]. The refinement of the predictions of protein-coding genes using cDNAs and ESTs has clearly improved the accuracy of the annotation of CDSs within large genomes [14]. In the absence of experimental data on gene expression or gene homology, several programs can be used to make ab initio gene predictions [22,23,24,25]
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