Communication Is Key: 5′–3′ Interactions that Regulate mRNA Translation and Turnover

Fakim, Hana; Fabian, Marc R.

doi:10.1007/978-3-030-31434-7_6

Cited by 10 publications

(17 citation statements)

References 95 publications

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“…Transcript-dependent factors, affecting the activation of deadenylation and translation inhibition processes, may also contribute to differences in the effectiveness of art-miRNA in different models of polyQ diseases. According to translation-dependent closed-loop model [73,74], it can be assumed that, although CAG repeats are in a very large distance from the poly(A) tail (especially for HTT transcript ~ 13 kb), art-miRNA-bound miRISCs are in close proximity to the poly(A) tails of polyQ disease-related mRNAs in cells (Fig. 6).…”

Section: Art-mirnas Activate Events Of Mrna Deadenylation and Translation Inhibitionmentioning

confidence: 99%

Artificial miRNAs targeting CAG repeat expansion in ORFs cause rapid deadenylation and translation inhibition of mutant transcripts

Ciesiolka

Stroynowska-Czerwinska

Joachimiak

et al. 2020

Cell. Mol. Life Sci.

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Polyglutamine (polyQ) diseases are incurable neurological disorders caused by CAG repeat expansion in the open reading frames (ORFs) of specific genes. This type of mutation in the HTT gene is responsible for Huntington’s disease (HD). CAG repeat-targeting artificial miRNAs (art-miRNAs) were shown as attractive therapeutic approach for polyQ disorders as they caused allele-selective decrease in the level of mutant proteins. Here, using polyQ disease models, we aimed to demonstrate how miRNA-based gene expression regulation is dependent on target sequence features. We show that the silencing efficiency and selectivity of art-miRNAs is influenced by the localization of the CAG repeat tract within transcript and the specific sequence context. Furthermore, we aimed to reveal the events leading to downregulation of mutant polyQ proteins and found very rapid activation of translational repression and HTT transcript deadenylation. Slicer-activity of AGO2 was dispensable in this process, as determined in AGO2 knockout cells generated with CRISPR-Cas9 technology. We also showed highly allele-selective downregulation of huntingtin in human HD neural progenitors (NPs). Taken together, art-miRNA activity may serve as a model of the cooperative activity and targeting of ORF regions by endogenous miRNAs.

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Section: Art-mirnas Activate Events Of Mrna Deadenylation and Translation Inhibitionmentioning

confidence: 99%

Artificial miRNAs targeting CAG repeat expansion in ORFs cause rapid deadenylation and translation inhibition of mutant transcripts

Ciesiolka

Stroynowska-Czerwinska

Joachimiak

et al. 2020

Cell. Mol. Life Sci.

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“…Intense research largely using in vitro translation systems provided ample yet indirect evidence for the closed-loop assisted reinitiation (hereafter abbreviated as CLAR): changes in polysome morphology, mRNA 3' tail involvement in the initiation process, etc. [18,31,34,35]. The data on synergetic 5' cap/3' poly(A)-dependent enhancement of protein synthesis described above, as well as computer modeling [36,37], suggest that it is CLAR that promotes a higher translation level by the increasing of the overall initiation rate.…”

Section: Introductionmentioning

confidence: 93%

“…Establishment of the closed-loop model [6] fueled the belief that the proximity of 5' and 3' termini should promote re-utilization of terminating ribosomes (or their small subunits only) at the same mRNA molecule, i.e., should lead to what can be called a functional cyclization of messenger RNAs [30][31][32][33]. Despite the general acceptance of the hypothesis, it has never been proved experimentally, mainly due to difficulties in monitoring the behavior of an individual ribosome.…”

Section: Introductionmentioning

confidence: 99%

Functional Cyclization of Eukaryotic mRNAs

Alekhina

Terenin

Dmitriev

et al. 2020

IJMS

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The closed-loop model of eukaryotic translation states that mRNA is circularized by a chain of the cap-eIF4E-eIF4G-poly(A)-binding protein (PABP)-poly(A) interactions that brings 5 and 3 ends together. This circularization is thought to promote the engagement of terminating ribosomes to a new round of translation at the same mRNA molecule, thus enhancing protein synthesis. Despite the general acceptance and the elegance of the hypothesis, it has never been proved experimentally. Using continuous in situ monitoring of luciferase synthesis in a mammalian in vitro system, we show here that the rate of translation initiation at capped and polyadenylated reporter mRNAs increases after the time required for the first ribosomes to complete mRNA translation. Such acceleration strictly requires the presence of a poly(A)-tail and is abrogated by the addition of poly(A) RNA fragments or m 7 GpppG cap analog to the translation reaction. The optimal functional interaction of mRNA termini requires 5 untranslated region (UTR) and 3 UTR of moderate lengths and provides stronger acceleration, thus a longer poly(A)-tail. Besides, we revealed that the inhibitory effect of the dominant negative R362Q mutant of initiation factor eIF4A diminishes in the course of translation reaction, suggesting a relaxed requirement for ATP. Taken together, our results imply that, upon the functional looping of an mRNA, the recycled ribosomes can be recruited to the start codon of the same mRNA molecule in an eIF4A-independent fashion. This non-canonical closed-loop assisted reinitiation (CLAR) mode provides efficient translation of the functionally circularized mRNAs.

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“…RNA fate is tightly coupled to the presence or absence of regulatory elements that direct RNA-protein interactions, localization and turnover rates. It is well established that from the moment an RNA emerges from the transcription machinery, it will undergo a number of modifications in both sequence and structure that will direct splicing, translocation, translation, and ultimately decay of mature transcripts [27][28][29]. As the cell has evolved to utilize RNA elements to regulate gene expression, so have viruses evolved to take advantage of them.…”

Section: Viral Endonuclease Targetingmentioning

confidence: 99%

Fated for decay: RNA elements targeted by viral endonucleases

Rodríguez

Macveigh-Fierro

Miles

et al. 2021

Seminars in Cell & Developmental Biology

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For over a decade, studies of messenger RNA regulation have revealed an unprecedented level of connectivity between the RNA pool and global gene expression. These connections are underpinned by a vast array of RNA elements that coordinate RNA-protein and RNA-RNA interactions, each directing mRNA fate from transcription to translation. Consequently, viruses have evolved an arsenal of strategies to target these RNA features and ultimately take control of the pathways they influence, and these strategies contribute to the global shutdown of the host gene expression machinery known as "Host Shutoff". This takeover of the host cell is mechanistically orchestrated by a number of non-homologous virally encoded endoribonucleases. Recent large-scale screens estimate that over 70 % of the host transcriptome is decimated by the expression of these viral nucleases. While this takeover strategy seems extraordinarily well conserved, each viral endonuclease has evolved to target distinct mRNA elements. Herein, we will explore each of these RNA structures/sequence features that render messenger RNA susceptible or resistant to viral endonuclease cleavage. By further understanding these targeting and escape mechanisms we will continue to unravel untold depths of cellular RNA regulation that further underscores the integral relationship between RNA fate and the fate of the cell.

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Communication Is Key: 5′–3′ Interactions that Regulate mRNA Translation and Turnover

Cited by 10 publications

References 95 publications

Artificial miRNAs targeting CAG repeat expansion in ORFs cause rapid deadenylation and translation inhibition of mutant transcripts

Artificial miRNAs targeting CAG repeat expansion in ORFs cause rapid deadenylation and translation inhibition of mutant transcripts

Functional Cyclization of Eukaryotic mRNAs

Fated for decay: RNA elements targeted by viral endonucleases

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