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Endogenous Stochastic Decoding of the CUG Codon by Competing Ser- and Leu-tRNAs in Ascoidea asiatica.

ABSTRACT: Although the "universal" genetic code is now known not to be universal, and stop codons can have multiple meanings, one regularity remains, namely that for a given sense codon there is a unique translation. Examining CUG usage in yeasts that have transferred CUG away from leucine, we here report the first example of dual coding: Ascoidea asiatica stochastically encodes CUG as both serine and leucine in approximately equal proportions. This is deleterious, as evidenced by CUG codons being rare, never at conserved serine or leucine residues, and predominantly in lowly expressed genes. Related yeasts solve the problem by loss of function of one of the two tRNAs. This dual coding is consistent with the tRNA-loss-driven codon reassignment hypothesis, and provides a unique example of a proteome that cannot be deterministically predicted. VIDEO ABSTRACT.

SUBMITTER: Muhlhausen S

PROVIDER: S-EPMC6041473 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Endogenous Stochastic Decoding of the CUG Codon by Competing Ser- and Leu-tRNAs in Ascoidea asiatica.

Mühlhausen Stefanie S Schmitt Hans Dieter HD Pan Kuan-Ting KT Plessmann Uwe U Urlaub Henning H Hurst Laurence D LD Kollmar Martin M

Current biology : CB 20180618 13

Although the "universal" genetic code is now known not to be universal, and stop codons can have multiple meanings, one regularity remains, namely that for a given sense codon there is a unique translation. Examining CUG usage in yeasts that have transferred CUG away from leucine, we here report the first example of dual coding: Ascoidea asiatica stochastically encodes CUG as both serine and leucine in approximately equal proportions. This is deleterious, as evidenced by CUG codons being rare, n ...[more]

PMID: 29910077

Similar Datasets

Yeast genetic codes - Endogenous Stochastic Decoding of the CUG Codon by Competing Ser- and Leu-tRNAs in Ascoidea asiatica

Project description:While the “universal” genetic code is now known not to be universal, and stop codons can have multiple meanings, one regularity remains, namely that for a given sense codon there is a unique translation. Examining CUG usage in yeasts that have transferred CUG away from leucine, we here report the first example of dual coding: Ascoidea asiatica stochastically encodes CUG as both serine and leucine. This is deleterious as evidenced by CUG codons being rare, never at conserved serine/leucine residues and predominantly in lowly expressed genes. Related yeasts solve the problem by loss-of-function of one of the two tRNAs. This dual-coding is consistent with the tRNA-loss driven codon reassignment hypothesis and provides a unique example of a proteome that cannot be deterministically predicted.

2018-06-13 | PXD009494 | Pride

Endogenous trans-translation structure visualizes the decoding of the first tmRNA alanine codon.

Project description:Ribosomes stall on truncated or otherwise damaged mRNAs. Bacteria rely on ribosome rescue mechanisms to replenish the pool of ribosomes available for translation. Trans-translation, the main ribosome-rescue pathway, uses a circular hybrid transfer-messenger RNA (tmRNA) to restart translation and label the resulting peptide for degradation. Previous studies have visualized how tmRNA and its helper protein SmpB interact with the stalled ribosome to establish a new open reading frame. As tmRNA presents the first alanine codon via a non-canonical mRNA path in the ribosome, the incoming alanyl-tRNA must rearrange the tmRNA molecule to read the codon. Here, we describe cryo-EM analyses of an endogenous Escherichia coli ribosome-tmRNA complex with tRNAAla accommodated in the A site. The flexible adenosine-rich tmRNA linker, which connects the mRNA-like domain with the codon, is stabilized by the minor groove of the canonically positioned anticodon stem of tRNAAla. This ribosome complex can also accommodate a tRNA near the E (exit) site, bringing insights into the translocation and dissociation of the tRNA that decoded the defective mRNA prior to tmRNA binding. Together, these structures uncover a key step of ribosome rescue, in which the ribosome starts translating the tmRNA reading frame.

| S-EPMC10944890 | biostudies-literature

Evolutionary instability of CUG-Leu in the genetic code of budding yeasts.

Project description:The genetic code used in nuclear genes is almost universal, but here we report that it changed three times in parallel during the evolution of budding yeasts. All three changes were reassignments of the codon CUG, which is translated as serine (in 2 yeast clades), alanine (1 clade), or the 'universal' leucine (2 clades). The newly discovered Ser2 clade is in the final stages of a genetic code transition. Most species in this clade have genes for both a novel tRNASer(CAG) and an ancestral tRNALeu(CAG) to read CUG, but only tRNASer(CAG) is used in standard growth conditions. The coexistence of these alloacceptor tRNA genes indicates that the genetic code transition occurred via an ambiguous translation phase. We propose that the three parallel reassignments of CUG were not driven by natural selection in favor of their effects on the proteome, but by selection to eliminate the ancestral tRNALeu(CAG).

| S-EPMC5951914 | biostudies-literature

Ser or Leu: structural snapshots of mistranslation in Candida albicans.

Project description:Candida albicans is a polymorphic opportunistic fungal pathogen normally residing as commensal on mucosal surfaces, skin and gastrointestinal and genitourinary tracts. However, in immunocompromised patients C. albicans can cause superficial mucosal infections or life-threatening disseminated candidemia. A change in physiological conditions triggers a cascade of molecular events leading to morphogenetic alterations and increased resistance to damage induced by host defenses. The complex biology of this human pathogen is reflected in its morphological plasticity and reinforced by the ability to ambiguously translate the universal leucine CUG codon predominantly as serine, but also as leucine. Mistranslation affects more than half of C. albicans proteome and it is widespread across many biological processes. A previous analysis of CTG-codon containing gene products in C. albicans suggested that codon ambiguity subtly shapes protein function and might have a pivotal role in signaling cascades associated with morphological changes and pathogenesis. In this review we further explore this hypothesis by highlighting the role of ambiguous decoding in macromolecular recognition of key effector proteins associated with the regulation of signal transduction cascades and the cell cycle, which are critical processes for C. albicans morphogenic plasticity under a variety of environmental conditions.

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Predicting the fungal CUG codon translation with Bagheera.

Project description:BackgroundMany eukaryotes have been shown to use alternative schemes to the universal genetic code. While most Saccharomycetes, including Saccharomyces cerevisiae, use the standard genetic code translating the CUG codon as leucine, some yeasts, including many but not all of the "Candida", translate the same codon as serine. It has been proposed that the change in codon identity was accomplished by an almost complete loss of the original CUG codons, making the CUG positions within the extant species highly discriminative for the one or other translation scheme.ResultsIn order to improve the prediction of genes in yeast species by providing the correct CUG decoding scheme we implemented a web server, called Bagheera, that allows determining the most probable CUG codon translation for a given transcriptome or genome assembly based on extensive reference data. As reference data we use 2071 manually assembled and annotated sequences from 38 cytoskeletal and motor proteins belonging to 79 yeast species. The web service includes a pipeline, which starts with predicting and aligning homologous genes to the reference data. CUG codon positions within the predicted genes are analysed with respect to amino acid similarity and CUG codon conservation in related species. In addition, the tRNACAG gene is predicted in genomic data and compared to known leu-tRNACAG and ser-tRNACAG genes. Bagheera can also be used to evaluate any mRNA and protein sequence data with the codon usage of the respective species. The usage of the system has been demonstrated by analysing six genomes not included in the reference data.ConclusionsGene prediction and consecutive comparison with reference data from other Saccharomycetes are sufficient to predict the most probable decoding scheme for CUG codons. This approach has been implemented into Bagheera (http://www.motorprotein.de/bagheera).

| S-EPMC4050208 | biostudies-literature

Two-codon T-box riboswitch binding two tRNAs.

Project description:T-box riboswitches control transcription of downstream genes through the tRNA-binding formation of terminator or antiterminator structures. Previously reported T-boxes were described as single-specificity riboswitches that can bind specific tRNA anticodons through codon-anticodon interactions with the nucleotide triplet of their specifier loop (SL). However, the possibility that T-boxes might exhibit specificity beyond a single tRNA had been overlooked. In Clostridium acetobutylicum, the T-box that regulates the operon for the essential tRNA-dependent transamidation pathway harbors a SL with two potential overlapping codon positions for tRNA(Asn) and tRNA(Glu). To test its specificity, we performed extensive mutagenic, biochemical, and chemical probing analyses. Surprisingly, both tRNAs can efficiently bind the SL in vitro and in vivo. The dual specificity of the T-box is allowed by a single base shift on the SL from one overlapping codon to the next. This feature allows the riboswitch to sense two tRNAs and balance the biosynthesis of two amino acids. Detailed genomic comparisons support our observations and suggest that "flexible" T-box riboswitches are widespread among bacteria, and, moreover, their specificity is dictated by the metabolic interconnection of the pathways under control. Taken together, our results support the notion of a genome-dependent codon ambiguity of the SLs. Furthermore, the existence of two overlapping codons imposes a unique example of tRNA-dependent regulation at the transcriptional level.

| S-EPMC3732954 | biostudies-literature

CUG start codon generates thioredoxin/glutathione reductase isoforms in mouse testes.

Project description:Mammalian cytosolic and mitochondrial thioredoxin reductases are essential selenocysteine-containing enzymes that control thioredoxin functions. Thioredoxin/glutathione reductase (TGR) is a third member of this enzyme family. It has an additional glutaredoxin domain and shows highest expression in testes. Herein, we found that human and several other mammalian TGR genes lack any AUG codons that could function in translation initiation. Although mouse and rat TGRs have such codons, we detected protein sequences upstream of them by immunoblot assays and direct proteomic analyses. Further gene engineering and expression analyses demonstrated that a CUG codon, located upstream of the sequences previously thought to initiate translation, is the actual start codon in mouse TGR. The use of this codon relies on the Kozak consensus sequence and ribosome-scanning mechanism. However, CUG serves as an inefficient start codon that allows downstream initiation, thus generating two isoforms of the enzyme in vivo and in vitro. The use of CUG evolved in mammalian TGRs, and in some of these organisms, GUG is used instead. The newly discovered longer TGR form shows cytosolic localization in cultured cells and is expressed in spermatids in mouse testes. This study shows that CUG codon is used as an inefficient start codon to generate protein isoforms in mouse.

| S-EPMC2836064 | biostudies-literature

Preferential ADP-ribosylation of arginine-3 in synthetic heptapeptide Leu-Arg-Arg-Ala-Ser-Leu-Gly.

Project description:Hen liver nuclear ADP-ribosyltransferase modified the synthetic heptapeptide Kemptide (Leu-Arg-Arg-Ala-Ser-Leu-Gly) at arginine-2 and/or arginine-3. Trypsin treatment of ADP-ribosyl-Kemptide revealed that the ADP-ribosylation of arginine-3 was constantly more abundant than that of arginine-2. ADP-ribosylation of Kemptide suppressed the subsequent phosphorylation by cyclic AMP-dependent protein kinase.

| S-EPMC1149392 | biostudies-other

Modification of orthogonal tRNAs: unexpected consequences for sense codon reassignment.

Project description:Breaking the degeneracy of the genetic code via sense codon reassignment has emerged as a way to incorporate multiple copies of multiple non-canonical amino acids into a protein of interest. Here, we report the modification of a normally orthogonal tRNA by a host enzyme and show that this adventitious modification has a direct impact on the activity of the orthogonal tRNA in translation. We observed nearly equal decoding of both histidine codons, CAU and CAC, by an engineered orthogonal M. jannaschii tRNA with an AUG anticodon: tRNAOpt We suspected a modification of the tRNAOptAUG anticodon was responsible for the anomalous lack of codon discrimination and demonstrate that adenosine 34 of tRNAOptAUG is converted to inosine. We identified tRNAOptAUG anticodon loop variants that increase reassignment of the histidine CAU codon, decrease incorporation in response to the histidine CAC codon, and improve cell health and growth profiles. Recognizing tRNA modification as both a potential pitfall and avenue of directed alteration will be important as the field of genetic code engineering continues to infiltrate the genetic codes of diverse organisms.

| S-EPMC5137457 | biostudies-literature

Proteogenomics analysis of CUG codon translation in the human pathogen Candida albicans.

Project description:BackgroundYeasts of the CTG-clade lineage, which includes the human-infecting Candida albicans, Candida parapsilosis and Candida tropicalis species, are characterized by an altered genetic code. Instead of translating CUG codons as leucine, as happens in most eukaryotes, these yeasts, whose ancestors are thought to have lost the relevant leucine-tRNA gene, translate CUG codons as serine using a serine-tRNA with a mutated anticodon, [Formula: see text]. Previously reported experiments have suggested that 3-5% of the CTG-clade CUG codons are mistranslated as leucine due to mischarging of the [Formula: see text]. The mistranslation was suggested to result in variable surface proteins explaining fast host adaptation and pathogenicity.ResultsIn this study, we reassess this potential mistranslation by high-resolution mass spectrometry-based proteogenomics of multiple CTG-clade yeasts, including various C. albicans strains, isolated from colonized and from infected human body sites, and C. albicans grown in yeast and hyphal forms. Our data do not support a bias towards CUG codon mistranslation as leucine. Instead, our data suggest that (i) CUG codons are mistranslated at a frequency corresponding to the normal extent of ribosomal mistranslation with no preference for specific amino acids, (ii) CUG codons are as unambiguous (or ambiguous) as the related CUU leucine and UCC serine codons, (iii) tRNA anticodon loop variation across the CTG-clade yeasts does not result in any difference of the mistranslation level, and (iv) CUG codon unambiguity is independent of C. albicans' strain pathogenicity or growth form.ConclusionsOur findings imply that C. albicans does not decode CUG ambiguously. This suggests that the proposed misleucylation of the [Formula: see text] might be as prevalent as every other misacylation or mistranslation event and, if at all, be just one of many reasons causing phenotypic diversity.

| S-EPMC8645108 | biostudies-literature

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