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PubMed2001

Forty years of decoding the silence in X-chromosome inactivation.

In 1961, Mary Lyon first put forth the hypothesis that one X chromosome is inactivated in each cell of the female mammal. As we enter the new millennium and complete 40 years of study, the field of X-inactivation is rich with ideas and many contrasting viewpoints. This review will focus on the random form of X-inactivation and present the latest views on its mechanism. Much attention has been focused on the genetic parsing of X-chromosome counting, choice, silencing and maintenance. It is now known that counting is functionally distinct from choice and that initiation and establishment of silencing are distinct from maintenance. Since Xist's seminal discovery 10 years ago, significant progress has been made towards understanding its function. Required only for initiation and establishment, Xist must act within a narrow developmental window, but its precise mode of action remains elusive. The ongoing search for Xist RNA-binding factors and effector proteins for silencing has led to members of the macroH2A family of histone variants. Finally, the recent discovery of Tsix implicates regulation of Xist expression by an antisense mechanism. Required for choice but not counting, Tsix blocks Xist RNA accumulation and hence blocks initiation of silencing on the future active X.

Animals↗
PubMed1999

The Candida albicans CUG-decoding ser-tRNA has an atypical anticodon stem-loop structure.

In many Candida species, the leucine CUG codon is decoded by a tRNA with two unusual properties: it is a ser-tRNA and, uniquely, has guanosine at position 33 (G33). Using a combination of enzymatic (V1 RNase, RnI nuclease) and chemical (Pb(2+), imidazole) probing of the native Candida albicans ser-tRNACAG, we demonstrate that the overall tertiary structure of this tRNA resembles that of a ser-tRNA rather than a leu-tRNA, except within the anticodon arm where there is considerable disruption of the anticodon stem. Using non-modified in vitro transcripts of the C. albicans ser-tRNACAG carrying G, C, U or A at position 33, we demonstrate that it is specifically a G residue at this position that induces the atypical anticodon stem structure. Further quantitative evidence for an unusual structure in the anticodon arm of the G33-tRNA is provided by the observed change in kinetics of methylation of the G at position 37, by purified Escherichia coli m(1)G37 methyltransferase. We conclude that the anticodon arm distortion, induced by a guanosine base at position 33 in the anticodon loop of this novel tRNA, results in reduced decoding ability which has facilitated the evolution of this tRNA without extinction of the species encoding it.

Anticodon↗
PubMed1996

Characterization of a B. subtilis minor isoleucine tRNA deduced from tDNA having a methionine anticodon CAT.

Bacillus subtilis, which belongs to Gram-positive eubacteria, has been predicted to have a minor isoleucine tRNA transcribed from the gene possessing the CAT anticodon, which corresponds to methionine. We isolated this tRNA and determined its sequence including modified nucleotides. Modified nucleotide analyses using TLC, UV, and FAB mass spectroscopy revealed that the first letter of the anticodon is modified to lysidine [4-amino-2-(N6-lysino)-1-beta-d-ribofuranosyl pyrimidine]. As a result, this tRNA agrees with the minor one predicted from the DNA sequence and is thought to decode the isoleucine codon AUA.

Acylation↗
PubMed1984

The sup8 tRNALeu gene of Schizosaccharomyces pombe has an unusual intervening sequence and reduced pairing in the anticodon stem.

We have cloned and sequenced the wild-type and suppressor alleles of the S. pombe sup8 tRNA gene. The wild-type allele has a leucine UAA anticodon and the suppressor (sup8-e) carries the opal suppressor anticodon UCA. The gene has a 16 base pair intervening sequence that, in the RNA, is predicted to form a secondary structure which involves base pairing to the 5', rather than the usual 3' side of the 5' splice site. When incubated in Saccharomyces cerevisiae cell-free extracts both alleles are efficiently transcribed, the 5' leader and 3' trailer sequences are removed and CCA is added to the 3' processed end; however, the intervening sequence is not excised. This finding implies that the structural requirements of the splicing endonucleases in the two yeasts have diverged. No other tRNA genes with related sequences were detected in S. pombe DNA by hybridization, suggesting that other UUA isoacceptors may be structurally dissimilar to sup8 or that the UUA codon may be decoded by a UUG leucine isoacceptor.

Alleles↗
PubMedDate not supplied

[Genomic polymorphism in the resolution of the fundamental and applied problems of microbiology and epidemiology].

As shown in this work, the methods of genomic fingerprinting make it possible to study genotypic links between strains, closely related phenotypically and genotypically, but having different epidemiological significance, to decode the mechanisms of the appearance and formation of epidemic strains, as well as to determine areas of their spread. The application principles of the methods of the study of genomic polymorphism for solving a number of fundamental problems of microbiology and epidemiology, as well as for carrying out effective retrospective and operative epidemiological analysis, are presented. Schemes for the genetic typing of a number of causative agents of bacterial infections are given. As an example, the optimum scheme of the identification and typing of Mycobacterium tuberculosis strains on the basis of polymerase chain reaction is presented and its advantages in comparison with the routine methods of laboratory diagnostics and typing are shown.

Animals↗
PubMed2004

HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells.

A T-cell subset, defined as CD4(+)CD25(hi) (regulatory T-cells [Treg cells]), was recently shown to suppress T-cell activation. We demonstrate that human Treg cells isolated from healthy donors express the HIV-coreceptor CCR5 and are highly susceptible to HIV infection and replication. Because Treg cells are present in very few numbers and are difficult to expand in vitro, we genetically modified conventional human T-cells to generate Treg cells in vitro by ectopic expression of FoxP3, a transcription factor associated with reprogramming T-cells into a Treg subset. Overexpression of FoxP3 in naïve human CD4(+) T-cells recapitulated the hyporesponsiveness and suppressive function of naturally occurring Treg cells. However, FoxP3 was less efficient in reprogramming memory T-cell subset into regulatory cells. In addition, FoxP3-transduced T-cells also became more susceptible to HIV infection. Remarkably, a portion of HIV-positive individuals with a low percentage of CD4(+) and higher levels of activated T-cells have greatly reduced levels of FoxP3(+)CD4(+)CD25(hi) T-cells, suggesting disruption of the Treg cells during HIV infection. Targeting and disruption of the T-cell regulatory system by HIV may contribute to hyperactivation of conventional T-cells, a characteristic of HIV disease progression. Moreover, the ability to reprogram human T-cells into Treg cells in vitro will greatly aid in decoding their mechanism of suppression, their enhanced susceptibility to HIV infection, and the unique markers expressed by this subset.

CD4-Positive T-Lymphocytes↗
PubMed2000

Pseudouridine in RNA: what, where, how, and why.

Pseudouridine (5-ribosyluracil) is a ubiquitous yet enigmatic constituent of structural RNAs (transfer, ribosomal, small nuclear, and small nucleolar). Although pseudouridine (psi) was the first modified nucleoside to be discovered in RNA, and is the most abundant, its biosynthesis and biological roles have remained poorly understood since its identification as a "fifth nucleoside" in RNA. Recently, a combination of biochemical, biophysical, and genetic approaches has helped to illuminate the structural consequences of psi in polyribonucleotides, the biochemical mechanism of U-->psi isomerization in RNA, and the role of modification enzymes (psi synthases) and box H/ACA snoRNAs, a class of eukaryotic small nucleolar RNAs, in the site-specific biosynthesis of psi. Through its unique ability to coordinate a structural water molecule via its free N1-H, psi exerts a subtle but significant "rigidifying" influence on the nearby sugar-phosphate backbone and also enhances base stacking. These effects may underlie the biological role of most (but perhaps not all) of the psi residues in RNA. Certain genetic mutants lacking specific psi residues in tRNA or rRNA exhibit difficulties in translation, display slow growth rates, and fail to compete effectively with wild-type strains in mixed culture. In particular, normal growth is severely compromised in an Escherichia coli mutant deficient in a pseudouridine synthase responsible for the formation of three closely spaced psi residues in the mRNA decoding region of the 23S rRNA. Such studies demonstrate that pseudouridylation of RNA confers an important selective advantage in a natural biological context.

Animals↗
PubMed2005

A reduced level of charged tRNAArgmnm5UCU triggers the wild-type peptidyl-tRNA to frameshift.

Frameshift mutations can be suppressed by a variety of differently acting external suppressors. The +1 frameshift mutation hisC3072, which has an extra G in a run of Gs, is corrected by the external suppressor mutation sufF44. We have shown that sufF44 and five additional allelic suppressor mutations are located in the gene argU coding for the minor tRNAArgmnm5UCU and alter the secondary and/or tertiary structure of this tRNA. The C61U, G53A, and C32U mutations influence the stability, whereas the C56U, C61U, G53A, and G39A mutations decrease the arginylation of tRNAArgmnm5UCU. The T-10C mutant has a base substitution in the -10 consensus sequence of the argU promoter that reduces threefold the synthesis of tRNAArgmnm5UCU . The lower amount of tRNAArgmnm5UCU or impaired arginylation, either independently or in conjunction, results in inefficient reading of the cognate AGA codon that, in turn, induces frameshifts. According to the sequence of the peptide produced from the suppressed -GGG-GAA-AGA- frameshift site, the frameshifting tRNA in the argU mutants is tRNAGlumnm5s2UUC, which decodes the GAA codon located upstream of the AGA arginine codon, and not the mutated tRNAArgmnm5UCU. We propose that an inefficient decoding of the AGA codon by a defective tRNAArgmnm5UCU stalls the ribosome at the A-site codon allowing the wild-type form of peptidyl-tRNAGlumnm5s2UUC to slip forward 1 nucleotide and thereby re-establish the ribosome in the 0-frame. Similar frame-shifting events could be the main cause of various phenotypes associated with environmental or genetically induced changes in the levels of aminoacylated tRNA.

Alleles↗
PubMed1998

A pseudouridine synthase required for the formation of two universally conserved pseudouridines in ribosomal RNA is essential for normal growth of Escherichia coli.

Escherichia coli rRNA contains 10 pseudouridines of unknown function. They are made by synthases, each of which is specific for one or more pseudouridines. Here we show that the sfhB (yfil) ORF of E. coli is a pseudouridine synthase gene by cloning, protein overexpression, and reaction in vitro with rRNA transcripts. Gene disruption by miniTn10(cam) insertion revealed that this synthase gene, here renamed rluD, codes for a synthase which is solely responsible in vivo for synthesis of the three pseudouridines clustered in a stem-loop at positions 1911, 1915, and 1917 of 23S RNA. The absence of RluD results in severe growth inhibition. Both the absence of pseudouridine and the growth defect could be reversed by insertion of a plasmid carrying the rluD gene into the mutant cell, clearly linking both effects to the absence of RIuD. This is the first report of a major physiological defect due to the deletion of any pseudouridine synthase. Growth inhibition may be due to the lack of one or more of the 23S RNA pseudouridines made by this synthase since pseudouridines 1915 and 1917 are universally conserved and are located in proximity to the decoding center of the ribosome where they could be involved in modulating codon recognition.

Amino Acid Sequence↗
PubMed1993

Competition between frameshifting, termination and suppression at the frameshift site in the Escherichia coli release factor-2 mRNA.

Competition between frameshifting, termination, and suppression at the frameshifting site in the release factor-2 (RF-2) mRNA was determined in vitro using a coupled transcription-translation system by adding a UGA suppressor tRNA. The expression system was programmed with a plasmid containing a trpE-prfB fusion gene so that each of the products of the competing events could be measured. With increasing concentrations of suppressor tRNA the readthrough product increased at the expense of both the termination and the frameshifting product indicating all three processes are in direct competition. The readthrough at the internal UGA termination codon was greater than that at the natural UGA termination codon at the end of the coding sequence. The results suggest that this enhanced suppression may reflect slower decoding of the internal stop codon by the release factor giving suppression a competitive advantage. The internal UGAC stop signal at the frameshift site has been proposed to be a relatively poor signal, but in addition the release factor may be less able to recognise the signal with the mRNA in such a constrained state. Consequently, the frameshifting event itself will be more competitive with termination in vivo because of this longer pause as the release factor is decoding the stop signal.

Base Sequence↗
PubMed2005

Increased prevalence of Mediterranean and Muslim populations in mutation-related research literature.

This paper assesses the prevalence of 569 population groups in mutation-related research literature by means of prevalence scores, calculated on the basis of a systematic search of the PubMed database. The main finding is that Mediterranean and Muslim populations are mentioned more often than other groups. The observed overrepresentation is attributed to the pervasiveness of hemoglobin disorders in these populations, the early decoding of hemoglobin and the relative commonness of consanguineous marriage in some of these populations. The paper points at potential benefits as well as predicaments that the intensive targeting of these populations for mutation research may entail.

Genetic Research↗
PubMed2001

Animal lectins: from initial description to elaborated structural and functional classification.

The genetic code connects the two biochemical dimensions of nucleic acids and proteins. Theoretical calculations on coding capacity reveal that oligosaccharides as hardware surpass peptides by more than seven orders of magnitude based on hexamer synthesis. Thus, the sugar code establishes the third dimension of biological information transfer. Using carbohydrate-binding proteins (lectins, enzymes and antibodies) the information content of such epitopes is decoded. Currently, five families of animal lectins are defined in structural terms. i.e. the C-type, I-type and P-type groups, the galectins and the pentraxins. They are involved in intra- and intercellular glycan routing using oligosaccharides as postal-code equivalents and acting as defense molecules homing in on foreign or aberrant glycosignatures, as crosslinking agent in biosignaling and as coordinator of transient or firm cell-cell/cell-matrix contacts. By delineating the driving forces toward complex formation, knowledge about the causes for specificity can be turned into design of custom-made high-affinity ligands for clinical application, e.g. in anti-adhesion therapy, drug targeting or diagnostic histopathology.

Animals↗
PubMed2005

A genome scan in multigenerational families with dyslexia: Identification of a novel locus on chromosome 2q that contributes to phonological decoding efficiency.

Dyslexia is a common and complex developmental disorder manifested by unexpected difficulty in learning to read. Multiple different measures are used for diagnosis, and may reflect different biological pathways related to the disorder. Impaired phonological decoding (translation of written words without meaning cues into spoken words) is thought to be a core deficit. We present a genome scan of two continuous measures of phonological decoding ability: phonemic decoding efficiency (PDE) and word attack (WA). PDE measures both accuracy and speed of phonological decoding, whereas WA measures accuracy alone. Multipoint variance component linkage analyses (VC) and Markov chain Monte-Carlo (MCMC) multipoint joint linkage and segregation analyses were performed on 108 families. A strong signal was observed on chromosome 2 for PDE using both VC (LOD=2.65) and MCMC methods (intensity ratio (IR)=32.1). The IR is an estimate of the ratio of the posterior to prior probability of linkage in MCMC analysis. The chromosome 2 signal was not seen for WA. More detailed mapping with additional markers provided statistically significant evidence for linkage of PDE to chromosome 2, with VC-LOD=3.0 and IR=59.6 at D2S1399. Parametric analyses of PDE, using a model obtained by complex segregation analysis, provided a multipoint maximum LOD=2.89. The consistency of results from three analytic approaches provides strong evidence for a locus on chromosome 2 that influences speed but not accuracy of phonological decoding.

Adolescent↗
PubMed2001

Five-base codons for incorporation of nonnatural amino acids into proteins.

Extension of the genetic code for the introduction of nonnatural amino acids into proteins was examined by using five-base codon-anticodon pairs. A streptavidin mRNA containing a CGGUA codon at the Tyr54 position and a tRNA(UACCG) chemically aminoacylated with a nonnatural amino acid were added to an Escherichia coli in vitro translation system. Western blot analysis indicated that the CGGUA codon is decoded by the aminoacyl-tRNA containing the UACCG anticodon. HPLC analysis of the tryptic fragment of the translation product revealed that the nonnatural amino acid was incorporated corresponding to the CGGUA codon without affecting the reading frame adjacent to the CGGUA codon. Another 15 five-base codons CGGN(1)N(2), where N(1) and N(2) indicate one of four nucleotides, were also successfully decoded by aminoacyl-tRNAs containing the complementary five-base anticodons. These results provide a novel strategy for nonnatural mutagenesis as well as a novel insight into the mechanism of frameshift suppression.

Amino Acid Sequence↗
PubMed1994

[Nucleotide sequence of the Escherichia coli B38 flagellin gene].

The fliC gene of the E. coli B38 flagellin has been cloned and its nucleotide sequence determined using the terminator method. According to the sequencing data, the flagellin contains 565 amino acid residues which exceeds by 65 residues the number of amino acid residues in the earlier decoded E. coli K12 flagellin. Strong homology was observed in the two flagellins among the 160 initial and 89 tail-ended residues, whereas the central, variable parts showed no homology. Similar to the K12 flagellin, the B38 flagellin has no serines, cysteines or tryptophans. The variable part of the fliC E. coli B38 gene contains a Chi-site which initiates the genetic recombination in E. coli and related species.

Amino Acid Sequence↗
PubMed2000

Decoding the human genome sequence.

The year 2000 is marked by the production of the sequence of the human genome. A 'working draft' of high quality sequence covering 90% of the genome has been determined and a quarter is in finished form, including the first two completed chromosomes. All sequence data from the project is made freely available to the community via the Internet, for further analysis and exploitation. The challenge which lies ahead is to decipher the information. Knowledge of the human genome sequence will enable us to understand how the genetic information determines the development, structure and function of the human body. We will be able to explore how variations within our DNA sequence cause disease, how they affect our interaction with our environment and ultimately to develop new and effective ways to improve human health.

Conserved Sequence↗
PubMed2002

High-resolution structures of large ribosomal subunits from mesophilic eubacteria and halophilic archaea at various functional States.

Structural analysis of the recently determined high resolution structures of the small and the large ribosomal subunits from three bacterial sources, assisted by the medium resolution structure of a complex of the entire ribosome with three tRNAs, led to a quantum jump in our understanding of the process of the translation of the genetic code into proteins. Results of these studies highlighted dynamic aspects of protein biosynthesis; illuminated the modes of action of several antibiotics; indicated strategies adopted by ribosomes for maximizing their functional activity and revealed a wealth of architectural elements, including long tails of proteins penetrating the particle s cores and stabilizing the intricate folds of the RNA chains. Binding of substrate analogues showed that the decoding and the peptide-bond formation are accomplished mainly by RNA. However, several proteins may be functionally relevant in directing the mRNA and in mediating the proper orientation of the tRNA molecules within the ribosomal rRNA frame. Elements involved in intersubunit contacts or in substrate binding are inherently flexible, but maintain well-ordered characteristic conformations in unbound particles. The ribosomes utilize this conformational variability for optimizing their efficiency and minimizing non-productive interactions, hence disorder of functionally relevant features may be linked to less active conformations or to far from physiological conditions. Clinically relevant antibiotics bind almost exclusively to rRNA. In the small subunit they affect the decoding accuracy or limit conformational mobility and in the large subunit they either interfere with substrate binding, by interacting with components of the peptidyl transferase cavity, or hinder the progression of the growing peptide chain.

Anti-Bacterial Agents↗