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Is there a translational mechanism that eukaryotes can use to produce different proteins from a single transcribed mRNA?

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    $\begingroup$ @RaghuParthasarathy I don't think the OP is referring to post-translational modification. It could be argued that PTM merely produces different forms of the same protein (same amino acid sequence). Some viruses can direct the synthesis of more than one protein from a single mRNA, where the multiple proteins are obtained by subsequent proteolysis (see here for a well-known example producing 3 proteins), but I suspect that is not what the OP has in mind either. $\endgroup$ – user1136 Oct 25 '19 at 17:02
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    $\begingroup$ Perhaps you are referring to polycistronic mRNA? $\endgroup$ – user1136 Oct 25 '19 at 17:51
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    $\begingroup$ @tyersome — You are being too restrictive In asking if the poster is referring to polycistronic mRNAs. The question is ok as it is, except it may well have been asked before. I’m not in a position to check. $\endgroup$ – David Oct 26 '19 at 0:35
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    $\begingroup$ @tyersome — There’s no reason to restrict an answer to one type or mechanism, especially as the poster doesn’t know the answer, and an answer would be more generally useful that covered polycistronic viral RNAs, alternative initiation, read-through, frameshift and post-translational proteolysis. I’m travelling at the moment, but if nobody finds the duplicate I feel exists, I’ll answer it comprehensively myself next week. $\endgroup$ – David Oct 26 '19 at 6:44
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    $\begingroup$ Possible duplicate of Can a single strand of mRNA form different polypeptide chains? $\endgroup$ – David Oct 28 '19 at 20:16
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There are multiple mechanisms that are known to lead to translation of substantially (or entirely) different proteins from a single mRNA. While these mechanisms are more typically seen in viruses, I'm focusing on examples documented within the endogenous transcriptome of eukaryotes.

Alternative translation initiation

One process that can lead to different proteins being translated from the same mRNA in eukaryotes is the use of alternative translation initiation sites.1,2 Translation typically starts with a pre-initiation complex recognizing the 5' cap and loading onto the mRNA. This complex scans until it finds an appropriate start site. The choice of start site depends on the how well the ribonucleotide sequence matches the Kozak consensus sequence.3 If the region around the first AUG is not a good match for that consensus then a process known as leaky scanning occurs and the pre-initiation complex can continue along the mRNA until a "good" start site is found.

While this can result in proteins with different functions, they will typically still have large regions of amino acid sequence in common. One example of this is in a kinase known as MK2, which is "a key regulator of transcription, migration, death signaling and post-transcriptional gene regulation".4

Polycistronic mRNAs

While more common in prokaryotes, in some cases eukaryotes also have polycistronic transcripts5,6. These transcripts encode multiple separate proteins (i.e. from independent open reading frames). The examples that I have found for mammals are all bicistronic (operons with two genes): LASS1-GDF1, SNRPN-SNURF, MTPN-LUZP6 and MFRP-C1QTNF5. You can search for those gene pairs, but there doesn't seem to be a huge amount of information available and in many cases one of the genes is almost completely uncharacterized. Eukaryotic operons (aka polycistronic mRNAs) are ubiquitous in trypanosomes, appear to be very common in nematodes (round worms), and are also frequently seen in Drosophila (a fly).6

Translational read-through

Translational readthrough aka. stop codon suppression occurs when an in frame stop codon is ignored either stochastically or under specific conditions and translation continues beyond that point. This leads to a C-terminal extension of the protein which in some cases has been shown to have functional implications7,8. An example of this is the [PSI+] prion in yeast, which promotes translational readthrough throughout the yeast transcriptome by inactivating a factor involved in translation termination.7

Translational frameshifts

This is well covered in the answer by @Dirigible.

References:

1: Kochetov, A. V. (2008). Alternative translation start sites and hidden coding potential of eukaryotic mRNAs. Bioessays, 30(7), 683-691.

2: Wan, J., & Qian, S. B. (2013). TISdb: a database for alternative translation initiation in mammalian cells. Nucleic acids research, 42(D1), D845-D850.

3: Acevedo, J. M., Hoermann, B., Schlimbach, T., & Teleman, A. A. (2018). Changes in global translation elongation or initiation rates shape the proteome via the Kozak sequence. Scientific reports, 8(1), 4018. 4: Trulley, P., Snieckute, G., Bekker-Jensen, D., Menon, M. B., Freund, R., Kotlyarov, A., ... & Gaestel, M. (2019). Alternative Translation Initiation Generates a Functionally Distinct Isoform of the Stress-Activated Protein Kinase MK2. Cell reports, 27(10), 2859-2870.

5: Tautz, D. (2008). Polycistronic peptide coding genes in eukaryotes—how widespread are they?. Briefings in Functional Genomics and Proteomics, 8(1), 68-74.

6: Blumenthal, T. (2004). Operons in eukaryotes. Briefings in Functional Genomics, 3(3), 199-211.

7: Schueren, F., & Thoms, S. (2016). Functional translational readthrough: a systems biology perspective. PLoS genetics, 12(8), e1006196.

8: Loughran, G., Jungreis, I., Tzani, I., Power, M., Dmitriev, R. I., Ivanov, I. P., ... & Atkins, J. F. (2018). Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response. Journal of Biological Chemistry, 293(12), 4434-4444.

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    $\begingroup$ I have found the question that this is a duplicate of. May I suggest about how your answer could have been improved. Its strong point is the references it gives, but as most readers will not follow them up or may not have access to all the papers, you could — in my opinion — improve the explanation in your commentary. Just saying "alternative translation" does not make it clear to the uninformed what you mean. The answer to the original by @WYSWYG is not perfect (IMHO), but he gets it right by referring to alternative initiation and mentioning sites. And he also mentions read-through. $\endgroup$ – David Oct 28 '19 at 20:27
  • $\begingroup$ @David — Thank you very much for all your valuable feedback and tireless work on maintaining standards on this site. Do you think it would be better to close this question as a duplicate? If you think is worthwhile to keep this question I'm happy to work on implementing your suggestions in my answer ... $\endgroup$ – tyersome Oct 30 '19 at 21:33
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    $\begingroup$ I had voted this as a duplicate (the text of my comment is autogenerated when one does that) but nobody else has seconded that — perhaps because the original is not specific to eukaryotes. My advice is to go ahead and improve your answer, explaining the basic Kozak mechanism in eukaryotes and how it has emerged that this is a simplification in many cases. If the question is ever closed as a duplicate I don't think you will loose your points, and you could always delete your answer and repost it on the original. $\endgroup$ – David Oct 31 '19 at 13:48
  • $\begingroup$ @David — Thank you for your encouragement! I finally found the time to put some more effort into this and while I'm not really satisfied I'm done for today. I welcome any further feedback you are willing to provide. $\endgroup$ – tyersome Nov 2 '19 at 3:09
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    $\begingroup$ That's fine. I do have a list of all the di- and tri-cistronic transcripts in Drosophila in supplementary material to a paper I published, but that would be a bit OTT. $\endgroup$ – David Nov 2 '19 at 12:38
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Separate from the alternative translation start site mechanism that tyersome describes is programmed translational frameshifting. This is independent of alternative splicing or post-translational modifications, and happens when a ribosome switches reading frames while a protein is already being translated. Typically, this phenomenon is associated with viral translation, and allows viruses to encode many proteins on relatively short genomes. Take HIV as an example: the polyprotein gag-pol requires efficient −1 frameshifting for expression of the individual gag and pol gene products.

In eukaryotes, examples are more sparse. Check out this review from 2012 --

... examples of mammalian genes that utilize −1 frameshifting are the mouse embryonic carcinoma differentiation regulated (EDR) gene and its human ortholog PEG10. A slippery sequence of G GGA AAC, in combination with a pseudoknot, mediates highly efficient −1 frameshifting, similar to viral frameshifting motifs (Clark et al., 2007). Recently, a programmed ribosomal −1 frameshift has been identified in the adenomatous polyposis coli (APC) mRNA in Caenorhabditis elegans that is mediated by a slippery sequence A AAA AAA or A AAA AAC (Baranov et al., 2011). The functional relevance of this frameshift is uncertain.

Frameshifting events are often mediated by conserved RNA secondary structures, like pseudoknots and stem-loops. For some specific examples of the types of structures involved in frameshifting, see the following publications:

Identification of a New Antizyme mRNA +1 Frameshifting Stimulatory Pseudoknot in a Subset of Diverse Invertebrates and its Apparent Absence in Intermediate Species

Structural probing and mutagenic analysis of the stem-loop required for Escherichia coli dnaX ribosomal frameshifting: programmed efficiency of 50%

−1 Frameshifting at a CGA AAG Hexanucleotide Site Is Required for Transposition of Insertion Sequence IS1222


Some more recent examples of (potential) programmed translational frameshifts in eukaryotes:

Search for potential reading frameshifts in cds from Arabidopsis thaliana and other genomes

Preprint: Extensive programmed ribosomal frameshifting in human as revealed by a massively parallel reporter assay

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    $\begingroup$ +1: This is a helpful addition, but your last two links are eubacterial rather than eukaryotic examples. Did you find any non-viral examples that have been shown to have functional significance in eukaryotes? $\endgroup$ – tyersome Nov 2 '19 at 3:05
  • $\begingroup$ Updated my answer to include more recent examples of programmed frameshifts in eukaryotes. Thanks, tyresome $\endgroup$ – Dirigible Nov 4 '19 at 14:48

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