Translational Control

Key Mechanistic Principles:

1. 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. 

2. THRB gene encodes at least 19 5'UTR mRNA variants (see Fig. 1a)

3. Long, highly folded 5' UTRs were frequently found to inhibit protein translation initiation (see literature).

4. 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.

5. 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.

6. 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:

7. 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. 

References:
    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.

Background (article): THRB (Thyroid Hormone Receptor Beta) produces at least 19 mRNA variants through alternative promoter usage and splicing. Most of these variants differ only in their 5′ UTRs and encode the same TRβ1 isoform, although their functional role remains unclear. Cells can also express functionally distinct TRβ2 and TRβ4 isoforms, which differ at the N- or C-termini of the proteins. Dysregulation of THRB expression, including altered translation of specific isoforms, can be influenced by the genomic context, such as the expression of overlapping genes within the same loci (TRHB/NR1D2), and has been observed in colorectal cancer, thyroid cancer, and other solid tumors, implicating disrupted 5′ UTR–mediated translational control in tumorigenesis.

Reference: 

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

Master A, Nauman A. Gene expression regulation by long naturally occurring antisense transcripts Post. Biol. Kom. 2014;41(1):3-28. Review. link, PDF [pl] Machine translated by google PDF [en]  

Master A, Nauman A. Genomic context and expression regulation of nuclear thyroid hormone receptors by long naturally occurring antisense transcripts. Post. Biol. Kom. 2014; 41(1):29-58. Review. link, PDF [pl] PDF [en]  

Key Mechanistic Principles of the project:

1. Regulome-Mediated Translational Control (RMTC) is the process by which the translational regulome, defined as a set of mRNAs containing similar cis-acting elements (uORFs, IRES, G-quadruplexes and other RNA structures) in untranslated regions (UTRs), coordinates the selective translation of transcripts in response to physiological and pathological conditions, including cell division, differentiation, and integrated stress response (ISR).

2. Within RMTC, these cis-acting elements are recognized and decoded by trans-acting factors (RNA-binding proteins, microRNAs, lncRNAs), which selectively regulate the translation of defined mRNA cohorts.

3. These interactions can be further modulated by RNA modifications, including epitranscriptomic marks, giving rise to Epitranscriptome-Mediated Translational Control (EMTRAC), which results in the selective translation of specific mRNAs and their associated transcript groups.

Concept: Protein synthesis is regulated through the interaction of RMTC and EMTRAC, which may explain the translatomic paradox and the functional significance of long, highly structured 5′ UTR mRNA variants, frequently expressed by oncogenes and tumor suppressors. Under basal conditions, these complex 5′ UTR variants may constitute a pool of translationally silent transcripts that can be rapidly recruited for translation via RMTC- and EMTRAC-mediated translatome reprogramming in response to physiological or stress signals.

For more details, see TRANSNIEP Project.

Backround (article):

Translation initiation is a key rate-limiting step in protein synthesis, with cap-dependent initiation being the predominant mechanism. Physiological (e.g., mitosis) and pathological (e.g., oxidative stress, hypoxia) conditions can switch translation to alternative, mRNA element–dependent mechanisms, such as IRES, uORF, IRE, CPE, DICE, AURE, CITE, or rHRE-mediated initiation. Hypoxia, in particular, can trigger adaptive responses including angiogenesis, myogenesis, tissue regeneration, and may contribute to cyclic protein synthesis in solid tumors. This review summarizes current knowledge of translational control with emphasis on alternative initiation pathways.

Master A, Nauman A. Molecular mechanisms of protein biosynthesis initiation - biochemical and biomedical implications of a new model of translation enhanced by the RNA hypoxia response element (rHRE) Postepy Biochem. 2014;60(1):39-54. Review. The Polish Biochemical Society has granted this work with Boleslaw Skarzynski Award for the best article published in a quarterly journal “Postepy Biochemii” published in year 2014.   PDF [Pl, En] 

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

Background:

Translational control (TC), a key but underexplored mechanism of protein synthesis regulation, plays a central role in stress adaptation and drug metabolism. Its dysregulation is linked to premature aging and civilization-related diseases, including cancer and cardiovascular disorders. By switching between cap-dependent and cap-independent mechanisms, TC allows cells to prioritize stress-response proteins under conditions such as hypoxia. Cancer cells exploit these switches via IRES to sustain oncogenic protein synthesis, while in cardiovascular disease TC enables rapid production of protective proteins during ischemic events. Dysregulated TC also impairs protein homeostasis, contributing to aging and neurodegeneration. This thematic issue highlights TC as a therapeutic target and presents cutting-edge approaches—including molecular modeling, advanced “omics,” and integrative bioinformatics—for developing next-generation therapies.