Synonymous Codons: Choose Wisely for Expression

Brule, Christina E.; Grayhack, Elizabeth J.

doi:10.1016/j.tig.2017.02.001

Cited by 182 publications

(147 citation statements)

References 133 publications

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“…In principle, codon usage changes in gag could affect gRNA translation [79]. However, the translation efficiency of a codon optimized gag mRNA is only ~ 1.6fold higher than wild type gag mRNA that contains theoretically suboptimal codon usage [80].…”

Section: Discussionmentioning

confidence: 99%

Increasing the CpG dinucleotide abundance in the HIV-1 genomic RNA inhibits viral replication

et al. 2017

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BackgroundThe human immunodeficiency virus type 1 (HIV-1) structural protein Gag is necessary and sufficient to form viral particles. In addition to encoding the amino acid sequence for Gag, the underlying RNA sequence could encode cis-acting elements or nucleotide biases that are necessary for viral replication. Furthermore, RNA sequences that inhibit viral replication could be suppressed in gag. However, the functional relevance of RNA elements and nucleotide biases that promote or repress HIV-1 replication remain poorly understood.ResultsTo characterize if the RNA sequence in gag controls HIV-1 replication, the matrix (MA) region was codon modified, allowing the RNA sequence to be altered without affecting the protein sequence. Codon modification of nucleotides (nt) 22-261 or 22-378 in gag inhibited viral replication by decreasing genomic RNA (gRNA) abundance, gRNA stability, Gag expression, virion production and infectivity. Comparing the effect of these point mutations to deletions of the same region revealed that the mutations inhibited infectious virus production while the deletions did not. This demonstrated that codon modification introduced inhibitory sequences. There is a much lower than expected frequency of CpG dinucleotides in HIV-1 and codon modification introduced a substantial increase in CpG abundance. To determine if they are necessary for inhibition of HIV-1 replication, codons introducing CpG dinucleotides were mutated back to the wild type codon, which restored efficient Gag expression and infectious virion production. To determine if they are sufficient to inhibit viral replication, CpG dinucleotides were inserted into gag in the absence of other changes. The increased CpG dinucleotide content decreased HIV-1 infectivity and viral replication.ConclusionsThe HIV-1 RNA sequence contains low abundance of CpG dinucleotides. Increasing the abundance of CpG dinucleotides inhibits multiple steps of the viral life cycle, providing a functional explanation for why CpG dinucleotides are suppressed in HIV-1.Electronic supplementary materialThe online version of this article (10.1186/s12977-017-0374-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Increasing the CpG dinucleotide abundance in the HIV-1 genomic RNA inhibits viral replication

et al. 2017

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“…The effects on translational efficiency are primarily mediated through the competition of cognate and near-cognate tRNA interactions, as dictated by the pool of charged tRNAs available in the cell (Elf et al, 2003;Gingold & Pilpel, 2011;Dana & Tuller, 2014). Moreover, codon usage biases, codon context, and interactions between adjacent codons have all been suggested to play a role in translational efficiency (Quax et al, 2015;Brule & Grayhack, 2017), though their direct effects on elongation are still not fully understood. Moreover, codon usage biases, codon context, and interactions between adjacent codons have all been suggested to play a role in translational efficiency (Quax et al, 2015;Brule & Grayhack, 2017), though their direct effects on elongation are still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

“…Individual codons that are generally decoded by more abundant tRNAs and are associated with increased translation efficiency have been defined as "optimal" (Sharp & Li, 1987;dos Reis et al, 2004;Burgess-Brown et al, 2008). Moreover, codon usage biases, codon context, and interactions between adjacent codons have all been suggested to play a role in translational efficiency (Quax et al, 2015;Brule & Grayhack, 2017), though their direct effects on elongation are still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism of translational stalling by inhibitory codon combinations and poly(A) tracts

et al. 2019

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Inhibitory codon pairs and poly(A) tracts within the translated mRNA cause ribosome stalling and reduce protein output. The molecular mechanisms that drive these stalling events, however, are still unknown. Here, we use a combination of in vitro biochemistry, ribosome profiling, and cryo-EM to define molecular mechanisms that lead to these ribosome stalls. First, we use an in vitro reconstituted yeast translation system to demonstrate that inhibitory codon pairs slow elongation rates which are partially rescued by increased tRNA concentration or by an artificial tRNA not dependent on wobble base-pairing. Ribosome profiling data extend these observations by revealing that paused ribosomes with empty A sites are enriched on these sequences. Cryo-EM structures of stalled ribosomes provide a structural explanation for the observed effects by showing decoding-incompatible conformations of mRNA in the A sites of all studied stall-and collision-inducing sequences. Interestingly, in the case of poly(A) tracts, the inhibitory conformation of the mRNA in the A site involves a nucleotide stacking array. Together, these data demonstrate a novel mRNA-induced mechanisms of translational stalling in eukaryotic ribosomes.

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“…There (31,32). Changes in biases of codon and mRNA secondary structure may affect mRNA stability, ribosomal translation, or protein folding (33). It remains to be determined whether these mutations in Rv0191, Rv3756c, and Rv1667c are associated with PZA resistance in clinical strains in future studies.…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Efflux Proteins Rv0191, Rv3756c, Rv3008, and Rv1667c Involved in Pyrazinamide Resistance in Mycobacterium tuberculosis

Zhang

Cui

et al. 2017

Antimicrob Agents Chemother

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Pyrazinamide (PZA) is a critical drug used for the treatment of tuberculosis (TB). PZA is a prodrug that requires conversion to the active component pyrazinoic acid (POA) by pyrazinamidase (PZase) encoded by the pncA gene. Although resistance to PZA is mostly caused by pncA mutations and less commonly by rpsA, panD, and clpC1 mutations, clinical strains without these mutations are known to exist. While efflux of POA was demonstrated in Mycobacterium tuberculosis previously, the efflux proteins involved have not been identified. Here we performed POA binding studies with an M. tuberculosis proteome microarray and identified four efflux proteins (Rv0191, Rv3756c, Rv3008, and Rv1667c) that bind POA. Overexpression of the four efflux pump genes in M. tuberculosis caused low-level resistance to PZA and POA but not to other drugs. Furthermore, addition of efflux pump inhibitors such as reserpine, piperine, and verapamil caused increased susceptibility to PZA in M. tuberculosis strains overexpressing the efflux proteins Rv0191, Rv3756c, Rv3008, and Rv1667c. Our studies indicate that these four efflux proteins may be responsible for PZA/POA efflux and cause PZA resistance in M. tuberculosis. Future studies are needed to assess their roles in PZA resistance in clinical strains.

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Synonymous Codons: Choose Wisely for Expression

Cited by 182 publications

References 133 publications

Increasing the CpG dinucleotide abundance in the HIV-1 genomic RNA inhibits viral replication

Increasing the CpG dinucleotide abundance in the HIV-1 genomic RNA inhibits viral replication

Molecular mechanism of translational stalling by inhibitory codon combinations and poly(A) tracts

Identification of Novel Efflux Proteins Rv0191, Rv3756c, Rv3008, and Rv1667c Involved in Pyrazinamide Resistance in Mycobacterium tuberculosis

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