Translational Control

INFORMATION AND LINKS

Fig.1a. The expression of mRNA variants of the TRHB suppressor gene. 5'UTR exons are marked with blue, coding sequence -red, 3'UTR -green. These 19 different 5' UTR variants were found to regulate the synthesis rate of 3 protein isoforms including 7 new variants (A2, A3, A4, F1, F2, IVS4B, IVS4A) and 2 unknown so far exons (1d1, miRHS) discovered by Adam Master. Most of the variants differ only in 5'UTR except of IVS4B that encodes truncated protein.

Fig.1b. Cis-acting elements (functional mRNA sequence domains) binding trans-acting factors (microRNAs, lncRNAs, RNA binding proteins, ASOs, dGoligos, eRNAs...), regulating the rate of protein synthesis.

For more details about targeting 5'UTR see my Inventions

The Role of mRNA 5' UTRs in the Expression of Tumor Suppressors.

A number of genes (including THRB, TP53, CDKN2A, ESR1...) encode multiple mRNA variants, which may vary predominantly in their non-coding sequences, whose role was largely unknown.
THRB gene encodes at least 19 5'UTR mRNA variants (see Fig. 1a)
Long, highly folded 5' UTRs were frequently found to inhibit protein translation initiation (see literature).
Different cis-acting elements (functional mRNA sequence domains) of at least 19 THRB 5' UTR mRNA variants can be targeted by various trans-acting factors (free nucleic acids and RNA binding proteins), including endogenous microRNAs and lncRNAs.
This interaction of 5' UTR cis-acting elements and trans-acting factors was found to control the protein synthesis rate, leading to altered (decreased or increased) protein levels.
Some trans-acting factors, such as microRNAs and lncRNAs binding to 5' UTR mRNAs, were found to elevate protein synthesis levels.

Well-documented concept and conclusion:

Highly folded 5' UTR mRNA variants may constitute translationally less (or non-) active transcripts that can be recruited for rapid and/or localized translation in the presence of specific endogenous or exogenous trans-acting factors recognizing cis-acting elements in these mRNAs (Doctoral Dissertation of Adam Master).

This Concept has been used in several inventions:

Master Adam. Nucleic acid molecule designed for selective enhancement of protein synthesis. Patent no. PL237080B1, 2010.

Cited by Roche's patent:

Johannes Braun, Ross Cordiner, Lukasz Kielpinski, Soren V Rasussen, Disa Elisabet Tehler. Application filed by F. Hoffmann-La Roche Ag, Hoffmann-La Roche Inc. Antisense oligonucleotide. WO2023111337A1, 2022.

Literature:

Master A, Wójcicka A, Piekiełko-Witkowska A, Bogusławska J, Popławski P, Tański Z, Darras VM, Williams GR, Nauman A. Untranslated regions of Thyroid hormone receptor beta 1 mRNA are impaired in human clear cell renal cell carcinoma. Biochim Biophys Acta. 2010 Nov;1802(11):995-1005. Epub 2010 Aug 3.

Master A, Wójcicka A, Giżewska K, Popławski P, Williams GR, Nauman A. A Novel Method for Gene-Specific Enhancement of Protein Translation by Targeting 5’UTRs of Selected Tumor Suppressors. PLoS ONE. 2016 May 12; 11(5): e0155359.

Master A, Nauman A. Gene expression regulation by long naturally occurring antisense transcripts Post. Biol. Kom. 2014;41(1):3-28. Review.

Fig.2. The expression of protein isoforms of the TRHB suppressor gene encoded by at least 19 mRNA variants. Three protein isoforms were found to differentially regulate the metabolism of clear cell renal cell carcinoma (ccRCC).

Master A, Nauman A. THRB (Thyroid Hormone Receptor, Beta). Atlas Genet Cytogenet Oncol Haematol. 2014; 18(6). PDF

Fig.3. General principles of translational control of protein translation.

MOLECULAR MECHANISMS

OF TRANSLATIONAL CONTROL OF PROTEIN SYNTHESIS

PROJECT PROPOSAL:
Translational Control: A Novel Frontier in Therapeutics for Civilization-Related Diseases and Premature Aging