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The NCBI report on the human huntingtin gene contains the following statement:

“This gene contains an upstream open reading frame in the 5' UTR that inhibits expression of the huntingtin gene product through translational repression.”

But no specific reference it given. Can anyone explain what this means.

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  • $\begingroup$ What I understood is that the promoter of the gene can only bind to repressors and inhibits translation. Am I right? $\endgroup$
    – Noob
    Feb 8, 2020 at 7:20
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    $\begingroup$ No. Please cite the source of your quotation. You say there are many mechanisms to achieve this, but do you know what “this” is? Do you know what translation is and what in a general sense repression would mean? (And how translation differs from transcription? Your talk of promotors suggests not. Or is it this particular example? In which case, as stated, give us your source. $\endgroup$
    – David
    Feb 8, 2020 at 8:32
  • $\begingroup$ @David ncbi.nlm.nih.gov/gene/3064 The last line of the Huntington gene summary is the source of the quotation. The reason why I say there are many mechanism for "this" is jbc.org/content/285/37/28506.full journals.plos.org/plospathogens/article?id=10.1371/… etc. I know the basic difference between transcription and translation. And repression, as I know, is the process of inhibitors binding to the promoter hence repressing transcription and translation. $\endgroup$
    – Noob
    Feb 8, 2020 at 11:45
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    $\begingroup$ No. Repression is a general English word meaning to subdue or put down, and a general molecular bioscience word to diminish or inhibit, which can be applied to many systems, and implies no mechanism and certainly does not require promoters, which are in no way involved in translation (at least in eukaryotes). I’ll look at the paper later. $\endgroup$
    – David
    Feb 8, 2020 at 13:02
  • $\begingroup$ @David oh..okay. Thanks! $\endgroup$
    – Noob
    Feb 8, 2020 at 13:14

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Summary

The statement refers to the small but significant translation of short open reading frames (ORFs) of huntingtin mRNA, 5′ to the main open reading frame that encodes the large (3144 amino acid) functional product of the mRNA (and gene). It has been reported that the translation of these short ORFs decreases (i.e. inhibits) the translation from the main ORF. It is implied that this is a mechanism for regulating the expression of the gene, and, as it occurs on the mRNA in the cytoplasm, it is an example of ‘translational regulation’ — specifically inhibition. The precise mechanism of this regulation — although not unique to this mRNA — is apparently unknown.

Translation of ORFs in eukaryotic mRNA

Most eukaryotic mRNAs are functionally monocistronic — i.e. they encode only a single protein — unlike bacterial mRNAs. Initiation of protein synthesis involves selection of an initiation codon (usually AUG) by a complex of initiator-tRNA and the small ribosome subunit, but, in contrast to prokaryotes, the mechanism in eukaryotes involves scanning along the mRNA from the 5′ end. In the majority of cases the initiation codon of the protein product is the first AUG, but the significant number of exceptions suggest an effect of sequence context or mRNA secondary structure.

In recent years evidence has accumulated that in cases where the first AUG is not that of the main protein product, a small amount of translation from such 5′ upstream ORFs does often occur.

Upstream ORF of eukaryotic mRNA

Diagrammatical representation of mRNA with upstream ORF (blue with initiation codon represented as an open triangle) and main ORF (black with initiation codon as closed triangle.)

Regulatory role of upstream ORFs

Johnstone et al. (2016) have reviewed a large body of evidence that indicates that upstream ORFs are translational repressors in eukaryotes. This has generally been established by measuring the extent of translation of the main ORF after manipulation or removal of the upstream ORFs. Much less is known about the actually mechanism of such regulation, which may vary from case to case, and certainly the paper on huntingtin only offered speculative possibilities. These include:

  • Binding of small peptide products of the upstream ORFs to the AUG of the main ORF
  • Pausing of ribosomal initiation complex at upstream ORFs impeding the progress of other to the AUG of the main ORF
  • Change of mRNA secondary structure by the binding of the ribosomal initiation complex at upstream ORFs increasing the difficulty of the initiation step in which the 5′ end is ’melted‘.

It also appears that the extent of the translation of upstream ORFs — and hence the extent of the repression — can itself be regulated by mechanisms such as the phosphorylation of initiation factor eIF2.

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  • $\begingroup$ Seems odd that translation occurs in the so called untranslated region. $\endgroup$
    – canadianer
    Feb 8, 2020 at 22:41
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    $\begingroup$ @canadianer — History. I didn't want to go into it in any more depth, but the initial assumption back in the 70s and 80s was that because mRNA was monocistronic (e.g. beta-globin) there was only one translated reading frame. It is obviously necessary to be able to name features of something one is discussing, and the regions of the mRNA 5' and 3' of the region coding for the protein were of interest — e.g. did they have any function regions, describing where the initiation complex started etc. At the time "untranslated region" (UTR) seemed appropriate. Knowledge changes, names stick. $\endgroup$
    – David
    Feb 8, 2020 at 23:29
  • $\begingroup$ Of course; just seemed amusing. $\endgroup$
    – canadianer
    Feb 9, 2020 at 0:18
  • $\begingroup$ @David Thank you very much for your insight. I am new to the subject and have no background so this was really helpful. $\endgroup$
    – Noob
    Feb 9, 2020 at 9:42

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