Reprogramming the genetic code: The emerging role of ribosomal frameshifting in regulating cellular gene expression

Advani, Vivek M.; Dinman, Jonathan D.

doi:10.1002/bies.201500131

Cited by 40 publications

(50 citation statements)

References 46 publications

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“…Indeed, pseudoknots constitute a well-known structural motif 87 in bacterial riboswitches and ribozymes and have roles in eukaryotic pre-mRNA processing such as in splicing 88,89 and adenosine-to-inosine editing 90 . Furthermore, there are prominent examples of cis- regulatory pseudoknots in the CDS that interact directly with translating ribosomes to induce programmed frameshifting (reviewed in REFS 91–93). Frameshifting pseudoknots can either lead to the production of different polypeptides, as first described in retroviruses 94–96 , or act as mRNA-destabilizing signals 92,97,98 embedded in coding regions that induce no-go decay or nonsense-mediated decay in eukaryotes.…”

Section: Higher-order Mrna Structuresmentioning

confidence: 99%

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

Leppek

Das

Barna

2017

Nat Rev Mol Cell Biol

617

645

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RNA molecules can fold into intricate shapes that can provide an additional layer of control of gene expression beyond that of their sequence. In this Review, we discuss the current mechanistic understanding of structures in 5′ untranslated regions (UTRs) of eukaryotic mRNAs and the emerging methodologies used to explore them. These structures may regulate cap-dependent translation initiation through helicase-mediated remodelling of RNA structures and higher-order RNA interactions, as well as cap-independent translation initiation through internal ribosome entry sites (IRESs), mRNA modifications and other specialized translation pathways. We discuss known 5′ UTR RNA structures and how new structure probing technologies coupled with prospective validation, particularly compensatory mutagenesis, are likely to identify classes of structured RNA elements that shape post-transcriptional control of gene expression and the development of multicellular organisms.

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Section: Higher-order Mrna Structuresmentioning

confidence: 99%

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

Leppek

Das

Barna

2017

Nat Rev Mol Cell Biol

617

645

View full text Add to dashboard Cite

show abstract

“…For example, programmed -1 ribosomal frameshifting (-1 PRF), a molecular mechanism in which cis-acting elements cause elongating ribosomes to slip backwards on mRNAs by one base, is emerging as a potentially important regulatory mechanism (reviewed in (32)). Key to regulation by -1 PRF is the finding that frameshift events on cellular mRNAs direct elongating ribosomes to premature termination codons, stimulating their rapid degradation by the nonsense-mediated mRNA decay (NMD) pathway (33). Thus dysregulation of -1 PRF can result in changes in gene expression.…”

Section: The Ribosome and Dysregulation Of Translational Controlmentioning

confidence: 99%

How Ribosomes Translate Cancer

et al. 2017

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A wealth of novel findings, including congenital ribosomal mutations in ribosomopathies and somatic ribosomal mutations in various cancers, have significantly increased our understanding of the relevance of ribosomes in oncogenesis. Here we explore the growing list of mechanisms by which the ribosome is involved in carcinogenesis – from the hijacking of ribosomes by oncogenic factors and dysregulated translational control, to the effects of mutations in ribosomal components on cellular metabolism. Of clinical importance, the recent success of RNA polymerase inhibitors highlights the dependence on “onco-ribosomes” as an Achilles’ heel of cancer cells and a promising target for further therapeutic intervention.

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“…They induce frameshift mutations, meaning that nucleotides are ‘missed’ during DNA and RNA polymerizations (Atkins et al, 2016). These triplets also cause ribosomal slippage during protein translation (Klobutcher and Farabaugh, 2002; Ketteler, 2012; Advani and Dinman, 2016). In other words, they mark programmed frameshifts for nucleotide polymerizations (DNA replication and RNA transcription) and translation.…”

Section: Introductionmentioning

confidence: 99%

Evolution of Nucleotide Punctuation Marks: From Structural to Linear Signals

Houmami

Seligmann

2017

Front. Genet.

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We present an evolutionary hypothesis assuming that signals marking nucleotide synthesis (DNA replication and RNA transcription) evolved from multi- to unidimensional structures, and were carried over from transcription to translation. This evolutionary scenario presumes that signals combining secondary and primary nucleotide structures are evolutionary transitions. Mitochondrial replication initiation fits this scenario. Some observations reported in the literature corroborate that several signals for nucleotide synthesis function in translation, and vice versa. (a) Polymerase-induced frameshift mutations occur preferentially at translational termination signals (nucleotide deletion is interpreted as termination of nucleotide polymerization, paralleling the role of stop codons in translation). (b) Stem-loop hairpin presence/absence modulates codon-amino acid assignments, showing that translational signals sometimes combine primary and secondary nucleotide structures (here codon and stem-loop). (c) Homopolymer nucleotide triplets (AAA, CCC, GGG, TTT) cause transcriptional and ribosomal frameshifts. Here we find in recently described human mitochondrial RNAs that systematically lack mono-, dinucleotides after each trinucleotide (delRNAs) that delRNA triplets include 2x more homopolymers than mitogenome regions not covered by delRNA. Further analyses of delRNAs show that the natural circular code X (a little-known group of 20 translational signals enabling ribosomal frame retrieval consisting of 20 codons {AAC, AAT, ACC, ATC, ATT, CAG, CTC, CTG, GAA, GAC, GAG, GAT, GCC, GGC, GGT, GTA, GTC, GTT, TAC, TTC} universally overrepresented in coding versus other frames of gene sequences), regulates frameshift in transcription and translation. This dual transcription and translation role confirms for X the hypothesis that translational signals were carried over from transcriptional signals.

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Reprogramming the genetic code: The emerging role of ribosomal frameshifting in regulating cellular gene expression

Cited by 40 publications

References 46 publications

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

How Ribosomes Translate Cancer

Evolution of Nucleotide Punctuation Marks: From Structural to Linear Signals

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