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PubMed1993

Detection of point mutations in the p53 gene: comparison of single-strand conformation polymorphism, constant denaturant gel electrophoresis, and hydroxylamine and osmium tetroxide techniques.

A comparison was made between the 3 most commonly used techniques for the detection of point mutations: single-strand conformation polymorphism (SSCP), constant denaturant gel electrophoresis (CDGE), and hydroxylamine and osmium tetroxide used in amplification mismatch cleavage analysis (HOT). Using human DNA samples containing known mutations in the p53 gene, SSCP detected 90% of mutations (18/20), CDGE detected 88% (15/17) pre-decoding of the samples but 100% when the mutations were known and the CDGE conditions optimized, and the HOT technique was 100% accurate, although 1 mutation was missed through careless examination of the gel. The positive and negative aspects of each of the techniques are considered and suggestions are made regarding the particular situations in which each of them is most useful.

DNA, Single-Stranded↗

PubMed2001

Hypothalamic neuropeptide mechanisms for regulating energy balance: from rodent models to human obesity.

In small rodents there is compelling evidence of a lipostatic system of body mass regulation in which peripheral signals of energy storage are decoded in the hypothalamus. The ability of small mammals to defend an appropriate mass against imposed energy imbalance has implicated hypothalamic neuroendocrine systems in body mass regulation. The effect of the neuropeptide systems involved in this regulation is primarily compensatory. However, small mammals can also effect changes in the level of body mass that they will defend, as exemplified by seasonal species. Regulatory control over fat mass may be relatively loose in humans; the sizes of long-term storage depots may not themselves be regulated, but rather may be a consequence of temporal variations in the matching of supply and demand. Whether food intake is regulated to match energy demand, or to match demand and to regulate storage, it is clear that physiological defects or genetic variation in hypothalamic and peripheral feedback systems will have profound implications for fat storage. Study of mechanisms implicated in energy homeostasis in laboratory rodents is likely to continue to identify targets for pharmacological manipulation in the management of human obesity.

Animals↗

PubMed2002

Insertions in the anticodon loop of tRNA1Gln(sufG) and tRNA(Lys) promote quadruplet decoding of CAAA.

Base insertion mutations in the anticodons of two different Escherichia coli tRNAs have been isolated that allow suppression of a series of +1 frameshift mutations. Insertion of a U between positions 34 and 35 of tRNAGln1 or addition of a G between positions 36 and 37 of tRNA(Lys) expand the anticodons of both tRNAs similarly to 3'-GUUU(-5') and allow decoding of complementary 5'-CAAA(-3') quadruplets. Analysis of the suppressed mRNA sequences suggests that suppression occurs by pairing of the expanded anticodons to all four bases of the complementary, quadruplet codon. The tRNA Gln mutants are identical to the sufG class of frameshift suppressors isolated both in Salmonella enterica serovar Typhimurium and E. coli by Kohno and Roth and previously thought to affect tRNA(Lys).

Anticodon↗

PubMed2000

Initiation factor 3-induced structural changes in the 30 S ribosomal subunit and in complexes containing tRNA(f)(Met) and mRNA.

Initiation factor 3 (IF3) acts to switch the decoding preference of the small ribosomal subunit from elongator to initiator tRNA. The effects of IF3 on the 30 S ribosomal subunit and on the 30 S.mRNA. tRNA(f)(Met) complex were determined by UV-induced RNA crosslinking. Three intramolecular crosslinks in the 16 S rRNA (of the 14 that were monitored by gel electrophoresis) are affected by IF3. These are the crosslinks between C1402 and C1501 within the decoding region, between C967xC1400 joining the end loop of a helix of 16 S rRNA domain III and the decoding region, and between U793 and G1517 joining the 790 end loop of 16 S rRNA domain II and the end loop of the terminal helix. These changes occur even in the 30 S.IF3 complex, indicating they are not mediated through tRNA(f)(Met) or mRNA. UV-induced crosslinks occur between 16 S rRNA position C1400 and tRNA(f)(Met) position U34, in tRNA(f)(Met) the nucleotide adjacent to the 5' anticodon nucleotide, and between 16 S rRNA position C1397 and the mRNA at positions +9 and +10 (where A of the initiator AUG codon is +1). The presence of IF3 reduces both of these crosslinks by twofold and fourfold, respectively. The binding site for IF3 involves the 790 region, some other parts of the 16 S rRNA domain II and the terminal stem/loop region. These are located in the front bottom part of the platform structure in the 30 S subunit, a short distance from the decoding region. The changes that occur in the decoding region, even in the absence of mRNA and tRNA, may be induced by IF3 from a short distance or could be caused by the second IF3 structural domain.

Alkalies↗

PubMed2006

P2 receptor web: complexity and fine-tuning.

The present review offers a new perspective on a family of receptors, termed P2 receptors, specific for nucleoside tri- and diphosphates of purines/pyrimidines. We emphasize here that while decoding the inputs of various related extracellular ligands, P2 receptors are a clear example of increasing biological complexity. They are represented by 7 ionotropic P2X and 8 metabotropic P2Y receptors; they have very heterogeneous ligands and binding characteristics, molecular properties, transduction mechanisms, cellular localization and protein-protein interactions. While the reason for this sophistication is unknown, a few compelling issues emerge while looking at such a rich variety. We ask, for instance, why so many different receptor subtypes are necessary for triggering biological properties and functions, and if these receptors are more than the sum of their single entities. A first possibility is that newly synthesized P2 proteins are casually located on the cell surface (stochastic hypothesis). Alternatively, distinct subunits are engaged on different cell phenotypes by genetic control (genetic determinism) and/or selective recruitment under physiopathological conditions and epigenetic stimuli (epigenetic determinism). Nevertheless, an appropriate way to both dissect the vast biological scenario and molecular complexity among P2 receptors and to integrate and upgrade their assortment is to regard them as a "combinatorial receptor web", that is, a dynamic architecture of P2 proteins demonstrating economic efficiency and involving a process of "fine-tuning", a mechanism which endorses the dynamic nature of all biological reactions. In the present analysis, we stimulate a scientific query about what contributes to such a vast P2 receptor sophistication.

Animals↗

PubMed2002

Antibiotics targeting ribosomes: crystallographic studies.

Resistance to antibiotics is a major problem in modern therapeutics. Ribosomes, the cellular organelle catalyzing the translation of the genetic code into proteins, are targets for several clinically relevant antibiotics. The ribosomes from eubacteria are excellent pathogen models. High resolution structures of the large and small ribosomal subunits were used as references that allowed unambiguous localization of almost a dozen antibiotic drugs, most of which are clinically relevant. Analyses of these structures showed a great diversity in the antibiotics' modes of action, such as interference with substrate binding, hindrance of the mobility required for the biosynthetic process and the blockage of tunnel which provides the path of exit for nascent proteins. All antibiotics studied by us were found to bind primarily to ribosomal RNA and, except for one allosteric effect, their binding did not cause major conformational changes. Antibiotics of the small ribosomal subunit may hinder tRNA binding, decoding, translocation, and the initiation of the entire biosynthetic process. The large subunit agents may target the GTPase center, interfere with peptide bond formation, or block the entrance of the nascent protein exit tunnel. The overall structure of the peptidyl transferase center and the modes of action of the antibiotic agents indicate that the ribosome serves as a template for proper positioning of tRNAs, rather than participating actively in the catalytic events associated with the creation of peptide bonds.

Anti-Bacterial Agents↗

PubMed2001

The mysteries of the human genome uncovered--medicine is changed forever.

It is impossible to overemphasize the significance of the recent announcement that 85% of the DNA of the human genome has been decoded. Physicians can now begin teasing out the secrets of human health and disease. Within the next 10 years, it may be possible to determine who may be vulnerable to illnesses like Alzheimer's disease, cancer, and diabetes. The world of medicine will be utterly transformed in a few decades. Even before decoding of the human genome is completed, scientists have begun a new and more challenging research in explaining the molecular basis of life. "Proteonomics," the cataloging and analysis of every protein in the human body looms as the next major scientific medical effort. Proteins are more varied and complex than DNA. Fifty years from now, our understanding of the human organism and its various ills will be transformed beyond recognition through genomics and proteonomics. Stay tuned!

Disease Management↗

PubMed1989

Alzheimer's disease and Down syndrome.

This report contains a summary of an extensive survey of autopsy data for mentally retarded persons. Among adults with DS, the brain neuropathology of AD was universal in those age 37 and over; claimed exceptions were indefensible. The behavioral evaluations of the DS adults, however, could be classified into three divisions: 1. "quiescent" (neither seizures nor dementia, 2). "partial" (seizures but no dementia), and 3). "active" (dementia +/- seizures). Thus, it is reasonable to argue that all persons with DS develop AD itself upon aging. However, DS cannot be used uncritically as an AD model since no increased incidence of active AD was found in DS with aging beyond the critical threshold age (mid-30's). Improved accurate quantification of Southern blots produced 100% accuracy in decoding blind samples of DS and non-DS samples. Using this system, DNA levels similar to those of DS have been demonstrated for all categories of AD at a small subsection of chromosome 21 near to, or within the DS DNA location on chromosome 21. Increased amounts of a complete, structural gene sequence were not found (or expected). The results provide evidence for a unitary hypothesis for DS and all forms of AD.

Adult↗

PubMed2001

CREB/CBP and SRE-interacting transcriptional regulators are fast on-off switches: duration of calcium transients specifies the magnitude of transcriptional responses.

Transient increases in the intracellular calcium concentration, which are associated with electrical activation of neurones, control synapse-to-nucleus communication. Calcium signals differ in time and space but it is unclear exactly how this translates into stimulus-specific gene expression. Analysis of transcription induced by calcium transients with defined durations revealed that the evoked genomic responses, unlike those following neurotrophin exposure, are not all-or-none but graded events. The CRE-binding protein CREB, its coactivator CREB-binding protein (CBP), and SRE-interacting transcriptional regulators are fast on-off switches: their activities are induced by short-lasting calcium signals, remain active for the duration of the signal and are rapidly shut-off after calcium concentrations have returned to basal levels. CREB is switched on by a fast, nuclear calmodulin (CaM) kinase-dependent mechanism that mediates CREB phosphorylation on serine 133 within 30 s of calcium entry. The second calcium-activated route to CREB involves the MAP kinase/extracellular signal-regulated kinase (ERK1/2) cascade. This pathway can be triggered by brief, 30-60 s calcium transients. ERK1/2 activity peaks several minutes after calcium entry and can outlast the calcium transient. The shut-off of CREB and ERK1/2 involves rapid dephosphorylation of their activator sites. These properties of transcription factors and their regulating kinases and phosphatases provide a mechanism through which the duration of calcium signals specifies the magnitude of the transcriptional response. The decoding of temporal features of calcium transients is likely to contribute to impulse-specific gene expression.

Animals↗

PubMed1999

Induced fit in initial selection and proofreading of aminoacyl-tRNA on the ribosome.

The fidelity of aminoacyl-tRNA (aa-tRNA) selection by the bacterial ribosome is determined by initial selection before and proofreading after GTP hydrolysis by elongation factor Tu. Here we report the rate constants of A-site binding of a near-cognate aa-tRNA. The comparison with the data for cognate aa-tRNA reveals an additional, important contribution to aa-tRNA discrimination of conformational coupling by induced fit. It is found that two rearrangement steps that limit the chemical reactions of A-site binding, i.e. GTPase activation (preceding GTP hydrolysis) and A-site accommodation (preceding peptide bond formation), are substantially faster for cognate than for near-cognate aa-tRNA. This suggests an induced-fit mechanism of aa-tRNA discrimination on the ribosome that operates in both initial selection and proofreading. It is proposed that the cognate codon-anticodon interaction, more efficiently than the near-cognate one, induces a particular conformation of the decoding center of 16S rRNA, which in turn promotes GTPase activation and A-site accommodation of aa-tRNA, thereby accelerating the chemical steps. As kinetically favored incorporation of the correct substrate has also been suggested for DNA and RNA polymerases, the present findings indicate that induced fit may contribute to the fidelity of template-programed systems in general.

Anticodon↗

PubMedDate not supplied

Organization and transcription of the mitochondrial ATP synthase genes in the yeast Yarrowia lipolytica.

Mitochondrial gene organization was studied in a dimorphic yeast, Yarrowia lipoltica. The gene order in a sequenced 6.6-kilobase region closely resembles that of the human mitochondrial genome in that ATP synthase subunit 8 and 6 genes are followed by genes for cytochrome c oxidase subunit 3 (which contains an intron), NADH-ubiquinone oxidoreductase subunit 4, and ATP synthase subunit 9. This region also contains tRNA genes decoding AUA, UGA, CUN and CCN codons, suggesting a unique mitochondrial translation. All the above genes are transcribed from the same DNA strand into multigenic RNAs, starting from a nonanucleotide sequence, 5'-ATATAAATA-3', similar to other yeast mitochondrial promoters.

Amino Acid Sequence↗

PubMed2005

Epigenetics--an epicenter of gene regulation: histones and histone-modifying enzymes.

The treatment of cancer through the development of new therapies is one of the most important challenges of our time. The decoding of the human genome has yielded important insights into the molecular basis of physical disorders, and in most cases a connection between failures in specific genes and the resulting clinical symptoms can be made. The modulation of epigenetic mechanisms enables, by definition, the alteration of cellular phenotype without altering the genotype. The information content of a single gene can be crucial or harmful, but the prerequisite for a cellular effect is active gene transcription. To this end, epigenetic mechanisms play a very important role, and the transcription of a given gene is directly influenced by the modification pattern of the surrounding histone proteins as well as the methylation pattern of the DNA. These processes are effected by different enzymes which can be directly influenced through the development of specific modulators. Of course, all genetic information is written as a four-character code in DNA. However, epigenetics describes the art of reading between the lines.

Acetylation↗

PubMed2006

Diverse bacterial genomes encode an operon of two genes, one of which is an unusual class-I release factor that potentially recognizes atypical mRNA signals other than normal stop codons.

BACKGROUND: While all codons that specify amino acids are universally recognized by tRNA molecules, codons signaling termination of translation are recognized by proteins known as class-I release factors (RF). In most eukaryotes and archaea a single RF accomplishes termination at all three stop codons. In most bacteria, there are two RFs with overlapping specificity, RF1 recognizes UA(A/G) and RF2 recognizes U(A/G)A. THE HYPOTHESIS: First, we hypothesize that orthologues of the E. coli K12 pseudogene prfH encode a third class-I RF that we designate RFH. Second, it is likely that RFH responds to signals other than conventional stop codons. Supporting evidence comes from the following facts: (i) A number of bacterial genomes contain prfH orthologues with no discernable interruptions in their ORFs. (ii) RFH shares strong sequence similarity with other class-I bacterial RFs. (iii) RFH contains a highly conserved GGQ motif associated with peptidyl hydrolysis activity (iv) residues located in the areas supposedly interacting with mRNA and the ribosomal decoding center are highly conserved in RFH, but different from other RFs. RFH lacks the functional, but non-essential domain 1. Yet, RFH-encoding genes are invariably accompanied by a highly conserved gene of unknown function, which is absent in genomes that lack a gene for RFH. The accompanying gene is always located upstream of the RFH gene and with the same orientation. The proximity of the 3' end of the former with the 5' end of the RFH gene makes it likely that their expression is co-regulated via translational coupling. In summary, RFH has the characteristics expected for a class-I RF, but likely with different specificity than RF1 and RF2. TESTING THE HYPOTHESIS: The most puzzling question is which signals RFH recognizes to trigger its release function. Genetic swapping of RFH mRNA recognition components with its RF1 or RF2 counterparts may reveal the nature of RFH signals. IMPLICATIONS OF THE HYPOTHESIS: The hypothesis implies a greater versatility of release-factor like activity in the ribosomal A-site than previously appreciated. A closer study of RFH may provide insight into the evolution of the genetic code and of the translational machinery responsible for termination of translation. REVIEWERS: This article was reviewed by Daniel Wilson (nominated by Eugene Koonin), Warren Tate (nominated by Eugene Koonin), Yoshikazu Nakamura (nominated by Eugene Koonin) and Eugene Koonin.

Journal Article↗

PubMed2003

Update on the language disorders of individuals on the autistic spectrum.

Inadequate language is a defining feature of the autism spectrum disorders (autism). Autism is a behaviorally and dimensionally defined developmental disorder of the immature brain that has a broad range of severity and many etiologies, with multiple genes involved. Early studies, which focused on the language of verbal children on the autistic spectrum, emphasized aberrant features of their speech such as unusual word choices, pronoun reversal, echolalia, incoherent discourse, unresponsiveness to questions, aberrant prosody, and lack of drive to communicate. Persistent lack of speech of some individuals was attributed to the severity of their autism and attendant mental retardation rather than possible inability to decode auditory language. Clinical study of unselected children with autism indicated that the language deficits of preschoolers fall into two broad types, perhaps with subtypes, those that involve reception and production of phonology (sounds of speech) and syntax (grammar), and those that do not but involve semantics (meaning) and pragmatics (communicative use of language, processing, and production of discourse). Except for the preschoolers' universally deficient pragmatics and comprehension of speech, many of their language deficits parallel those of non-autistic preschoolers with developmental language disorders. There is now biological support for the clinical observation that young autistic children are language disordered as well as autistic. Recent electrophysiological studies disclose auditory input abnormalities in lateral temporal cortex even in verbal individuals on the autistic spectrum. Severe receptive deficits for phonology enhance the risk for epilepsy. Genetic studies indicate that linkage to chromosome 7q31-33 is limited to families with evidence for phonologic impairment as well as autism. Clearly, social and cognitive disorders alone provide an inadequate explanation for the range of language deficits in autism.

Auditory Perception↗

PubMed2004

Decoding hematopoietic specificity in the helix-loop-helix domain of the transcription factor SCL/Tal-1.

The helix-loop-helix (HLH) domain is employed by many transcription factors that control cell fate choice in multiple developmental settings. Previously, we demonstrated that the HLH domain of the class II basic HLH (bHLH) protein SCL/Tal-1 is critical for hematopoietic specification. We have now identified residues in this domain that are essential for restoring hematopoietic development to SCL-/- embryonic stem cells and sufficient to convert a muscle-specific HLH domain to one able to rescue hematopoiesis. Most of these critical residues are distributed in the loop of SCL, with one in helix 2. This is in contrast to the case for MyoD, the prototype of class II bHLH proteins, where the loop seems to serve mainly as a linker between the two helices. Among the identified residues, some promote heterodimerization with the bHLH partners of SCL (E12/E47), while others, unimportant for this property, are still crucial for the biological function of SCL. Importantly, the residue in helix 2 specifically promotes interaction with a known partner of SCL, the LIM-only protein LMO2, a finding that strengthens genetic evidence that these proteins interact. Our data highlight the functional complexity of bHLH proteins, provide mechanistic insight into SCL function, and strongly support the existence of an active SCL/LMO2-containing multiprotein complex in early hematopoietic cells.

Adaptor Proteins, Signal Transducing↗

PubMed1997

Specific binding of aminoglycosides to a human rRNA construct based on a DNA polymorphism which causes aminoglycoside-induced deafness.

RNA constructs prepared from wild-type and mutant (1555(G)) human mitochondrial 12S RNA were studied with respect to their abilities to specifically bind aminoglycoside antibiotics. The 1555(G) point mutation had previously been found to be associated with hereditary deafness induced by aminoglycosides. It is shown here that the 1555(G) RNA analog stoichiometrically binds aminoglycosides with high affinities, while the wild-type construct does not bind aminoglycosides at all. Analogous mutations in a 16S bacterial rRNA construct show the opposite behavior. Bacterial 16S rRNA constitutes the functional target for aminoglycoside antibiotics. While the wild-type 16S rRNA decoding region construct binds aminoglycosides stoichiometrically with binding affinities in the micromolar range, the mutant is unable to specifically bind aminoglycosides. These results demonstrate the importance of a specific GC base pair in aminoglycoside binding in both the human and the bacterial rRNA constructs. These studies also provide quantitative evidence in support of the hypothesis that the 1555(G) point mutation in human mitochondrial 12S RNA causes aminoglycoside induced deafness.

Aminoglycosides↗

PubMed2026

An expanded codebook of human transcription factor DNA-binding specificity.

Gene expression is regulated by transcription factors (TFs), which recognize specific DNA sequence motifs. Several hundred putative human TFs, identified mainly by an apparent DNA-binding domain, lack known binding motifs1. Furthermore, even for well-characterized TFs, it remains controversial the degree to which motifs accurately reflect binding sites in living cells2. Here we describe a systematic effort ('Codebook') to determine the sequence specificity of 332 putative and poorly characterized human TFs. More than 4,000 independent experiments, encompassing multiple in vitro and in vivo assays, produced motifs for just over half (177; 53%) of the TFs, of which most are associated with only a single protein. These results extend the vocabulary of sequence recognition encoded by human TFs by around 130 distinct motifs. Moreover, binding motifs identified in vitro are strongly enriched in cellular binding sites. Collectively, the data reveal tens of thousands of previously unknown, conserved and direct TF-binding sites across the human genome. These sites are concentrated in promoter regions and are predictive of gene expression. In summary, this new codebook provides an important step forward in decoding the human genome.

Humans↗

PubMed2025

Decoding the distribution, structure-function-redox potential relationship and recent advances in fungal laccases: a systematic approach.

Laccases, categorized as multicopper oxidases, are recognized for their multifaceted roles in ecosystems and their utility in diverse industrial applications. Laccases from higher fungi, specifically Ascomycota and Basidiomycota, have garnered significant research interest due to their elevated redox potentials and their capacity to degrade lignin in decaying wood, alongside other industrial uses. Here, we have conducted a comprehensive and systematic analysis on fungal laccases using Web of Science, Scopus, PubMed, and ScienceDirect. The genomic distribution, phylogenetic affiliation, and structural organization of laccase-encoding genes in higher fungal species were investigated, as were the catalytic mechanisms of the corresponding enzymes. Additionally, the study explores the correlation between structural domains and redox potential, as well as the impact of post-translational modifications like glycosylation on enzyme activity. Furthermore, the recent advancements in laccase engineering, employing strategies such as rational design, directed evolution, and heterologous expression are discussed. The review also explores the scope of "artificial intelligence and machine learning" in deducing the structure-function relationships, optimizing codon usage, predicting signal peptides, enhancing enzymatic performance, and developing host-specific genetic engineering techniques is also discussed for tailoring fungal laccases to meet the demands of industrial biocatalysis for improved activity and stability.

Laccase↗