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PubMed1998

[Molecular cell biology--basis for new diagnostic and therapeutic approaches in surgical oncology].

In the past two decades increasing research efforts have focused on the molecular biology of the cell. In the beginning, these research activities were purely academic without any direct clinical relation. A series of important discoveries, initiated particularly by the unravelling of the genetic code and the discovery of the molecular basis of gene expression and genetics, the subsequent identification of oncogenes and tumor suppressor genes and finally the description of major mechanisms which induce genetic instability in cells, now indicate the way to many new diagnostic and therapeutic strategies. In surgical oncology, these attempts are yielding the first clinical consequences. Basic aspects of molecular cell biology as far as they are relevant for surgical oncologists are discussed.

Cell Transformation, Neoplastic↗

PubMed1996

Recoding: dynamic reprogramming of translation.

A minority of genes in probably all organisms rely on "recoding" for translation of their mRNAs. In these cases, the rules for decoding are temporarily altered through the action of specific signals built into the mRNA sequences. Three classes are described. 1. Frameshifting at a particular site allows expression of a protein from an mRNA with overlapping open reading frames, often giving two protein products from one mRNA. 2. The meanings of code words are altered: specific stop codons can be redirected to encode selenocysteine, tryptophan, or glutamine. 3. Ribosomes can translate over coding gaps in mRNA. These novel mechanisms expand the repertoire of the genetic code and are at the heart of several regulatory schemes.

Animals↗

PubMed2004

The problem of amino acid complementarity and antisense peptides.

The review presents three hypotheses concerning the amino acid complementarity: 1) the Mekler-Blalock antisense hypothesis; 2) the Root-Bernstein approach based on stereochemical complementarity of amino acids and anti-amino acids coded by anticodons read in parallel with the coding DNA strand; 3) Siemion hypothesis resulting from the periodicity of the genetic code. The current state of knowledge as well as the results of the implementations of these hypotheses are compared. A special attention is given to Root-Bernstein and Siemion hypotheses, which differ in only few points of the complementarity prediction. We describe methods of investigation of peptide-antipeptide pairing, including circular dichroism, mass spectrometry, affinity chromatography and other techniques. The biological applications of complementarity principle are considered, such as search for bioeffector-bioreceptor interaction systems, the influence of peptide-antipeptide pairing on the activity of peptide hormones, and the application of antipeptides in immunochemistry. The possible role of amino acid-anti-amino acid interactions in the formation of the spatial structures of peptides, proteins and protein complexes is discussed. Such problems as the pairing preferences of protein-protein interfaces, the role of the pairing in the creation of disulfide bonds and the possible appearance of such interactions in beta-structure are also examined. The main intention of the paper is to bring the complementarity problem to the attention of the scientific community, as a possible tool in proteomics, molecular design and molecular recognition.

Amino Acid Sequence↗

PubMed1996

[Gene therapy in cardiovascular medicine: reality or fantasy?].

Since the discovery of DNA and the genetic code the main goals of molecular medicine have been: to understand the genetic basis of diseases, and to develop strategies capable of providing long-term cure. In the last 2 decades methodological progress has made it technically feasible to pursue both these goals. In its classical conception gene therapy consists in the introduction of genes into somatic cells in order to correct a specific genetic defect or to provide cells with a new function which will ultimately result to be advantageous for the patient. These strategies have been proposed for the treatment of numerous diseases, both hereditary, mono- or polygenic, and acquired in nature. The purpose of this review is to discuss the problems inherent in gene therapy, currently pursued strategies and future clinical perspectives.

Cardiovascular Diseases↗

PubMed1996

Single sequence of a helix-loop peptide confers functional anticodon recognition on two tRNA synthetases.

The specific aminoacylation of RNA oligonucleotides whose sequences are based on the acceptor stems of tRNAs can be viewed as an operational RNA code for amino acids that may be related to the development of the genetic code. Many synthetases also have direct interactions with tRNA anticodon triplets and, in some cases, these interactions are thought to be essential for aminoacylation specificity. In these instances, an unresolved question is whether interactions with parts of the tRNA outside of the anticodon are sufficient for decoding genetic information. Escherichia coli isoleucyl- and methionyl-tRNA synthetases are closely related enzymes that interact with their respective anticodons. We used binary combinatorial mutagenesis of a 10 amino acid anticodon binding peptide in these two enzymes to identify composite sequences that would confer function to both enzymes despite their recognizing different anticodons. A single peptide was found that confers function to both enzymes in vivo and in vitro. Thus, even in enzymes where anticodon interactions are normally important for distinguishing one tRNA from another, these interactions can be 'neutralized' without losing specificity of amino-acylation. We suggest that acceptor helix interactions may play a role in providing the needed specificity.

Amino Acid Sequence↗

PubMed1997

Killing two birds with one stone: a chemically plausible scheme for linked nucleic acid replication and coded peptide synthesis.

To understand how life began, we must explain the origins of nucleic acid replication and genetically coded peptide synthesis. Neither of these is easy to explain individually; here, we propose a chemically plausible scheme for the evolution of a process that simultaneously produced both polymers. Later, two separate machineries could have evolved from the linked process.

DNA Replication↗

PubMed1994

The complete mitochondrial DNA sequence of the crustacean Artemia franciscana.

The complete mitochondrial DNA (mtDNA) sequence of the brine shrimp Artemia franciscana has been determined. It extends the present knowledge of mitochondrial genomes to the crustacean class and supplies molecular markers for future comparative studies in this large branch of the arthropod phylum. Artemia mtDNA is 15,822 nucleotides long, and when compared with its Drosophila counterpart, it shows very few gene rearrangements, merely affecting two tRNAs placed 3' downstream of the ND 2 gene. In this position a stem-loop secondary structure with characteristics similar to the vertebrate mtDNA L-strand origin of replication is found. This suggests that, associated with tRNA changes, the diversification of the mitochondrial genome from an ancestor common to crustacea and insects could be explained by errors in the mtDNA replication process. Although the gene content is the same as in most animal mtDNAs, the sizes of the protein coding genes are in some cases considerably smaller. Artemia mtDNA uses the same genetic code as found in insects, ATN and GTG are used as initiation codons, and several genes end in incomplete T or TA codons.

Animals↗

PubMed2003

Limitations of allotopic expression of mitochondrial genes in mammalian cells.

The possibility of expressing mitochondrial DNA-coded genes in the nuclear-cytoplasmic compartment provides an attractive system for genetic treatment of mitochondrial disorders associated with mitochondrial DNA mutations. In theory, by recoding mitochondrial genes to adapt them to the universal genetic code and by adding a DNA sequence coding for a mitochondrial-targeting sequence, one could achieve correct localization of the gene product. Such transfer has occurred in nature, and certain species of algae and plants express a number of polypeptides that are commonly coded by mtDNA in the nuclear-cytoplasmic compartment. In the present study, allotopic expression of three different mtDNA-coded polypeptides (ATPase8, apocytochrome b, and ND4) into COS-7 and HeLa cells was analyzed. Among these, only ATPase8 was correctly expressed and localized to mitochondria. The full-length, as well as truncated forms, of apocytochrome b and ND4 decorated the periphery of mitochondria, but also aggregated in fiber-like structures containing tubulin and in some cases also vimentin. The addition of a hydrophilic tail (EGFP) to the C terminus of these polypeptides did not change their localization. Overexpression of molecular chaperones also did not have a significant effect in preventing aggregations. Allotopic expression of apocytochrome b and ND4 induced a loss of mitochondrial membrane potential in transfected cells, which can lead to cell death. Our observations suggest that only a subset of mitochondrial genes can be replaced allotopically. Analyses of the hydrophobic patterns of different polypeptides suggest that hydrophobicity of the N-terminal segment is the main determinant for the importability of peptides into mammalian mitochondria.

Animals↗

PubMedDate not supplied

Genomic medicine in Mexico. Applications of gene therapy for cirrhosis reversion.

Genomic medicine represents a powerful armamentarium to tackle down most of chronic diseases which have not, so far, defeated. Thus, this new and powerful biotechnologic set of weapons enable us to make use of molecular diagnostic to detect silent diseases, otherwise undetectable by conventional analysis. Moreover, elucidation of the complete and final draft of the human genome code will allow, although not in this decade, the design of specific farmaco-genetic treatments for patients on basis of their individual genetic code. Regarding new medical treatments, gene therapy as emerged as a true hope for treatment of many chronic diseases. 636 FDA-.approved clinical protocols are currently undergoing and sooner than later we ll be witness of the results

Genetic Therapy↗

PubMed1984

Molecular homogeneity of heat-stable enterotoxins produced by bovine enterotoxigenic Escherichia coli.

Heat-stable enterotoxins (STs) from four strains of bovine enterotoxigenic Escherichia coli representing four serogroups were purified to homogeneity by utilizing previously published purification schemata. Biochemical characterization of the purified STs showed that they met the basic criteria for the heat-stable enterotoxins of E. coli. Amino acid analysis of the purified STs revealed that they were peptides of identical amino acid composition. This composition consisted of 18 residues of 10 different amino acids, 6 of which were cysteine. The amino acid composition of the four ST peptides was identical to that reported for the STs of human and porcine E. coli. In addition, complete sequence analysis of two of the ST peptides and partial sequencing of several others revealed strong homology to the sequences of STs from human and porcine E. coli and to the sequence predicted from the last 18 codons of the transposon Tn1681. There was also substantial homology to the sequence predicted from the ST-coding genetic element of human E. coli, which may indicate the existence of identical bioactive configuration among ST peptides of E. coli strains of various host origins. These data support the hypothesis that STs produced by human, bovine, and porcine E. coli are coded by a closely related genetic element which may have originated from a single, widely disseminated transposon.

Amino Acid Sequence↗

PubMed1999

Screening for hereditary cancer and genetic testing, epitomized by breast cancer.

The new genetics is having an impact on many areas of healthcare. Diversity in the genetic code accounts for differences in phenotypes between populations and it is becoming apparent that genetic differences may have a role in predisposition to and behaviour of disease. Genetic models suggest that there are two types of genetic predisposition to disease: the so-called high and low penetrance genes. At present, most of the impact on medicine has been from highly penetrant genes, and genetic testing for disease predisposition, particularly for diseases of late onset (e.g. certain cancers) is in its infancy. As a general statement, approximately 5-10% of common cancers are due to such highly penetrant genes. The category of genes that will become of increasing interest is that of the low penetrance genes. Often these are normal variations in genes that result in a slightly increased risk of disease. These are analogous to high blood pressure carrying an increased risk of cardiovascular disease. Once rapid genetic analysis is available for these types of genes, such analysis would be analogous to taking someone's blood pressure in a general practitioner's (GP's) surgery to identify individuals at increased risk of cardiovascular disease. This will produce a revolutionary change in the way we practise medicine. Genetic analysis will become faster and may therefore be more commonplace. It is possible to envisage an era when genetic analysis will become a routine part of primary care to identify changes in low penetrance genes that will confer a 'risk profile' for patients. This will then enable their primary care physicians to advise about primary prevention and even prescribe certain preventive drugs to decrease the risk of certain diseases occurring. This proactive rather than reactive style of practising medicine is potentially exciting, however it carries with it ethical, legal and social implications for how we deal with this new knowledge.

Adult↗

PubMed1989

Codon usage and secondary structure of MS2 phage RNA.

MS2 is an RNA bacteriophage (3569 bases). The secondary structure of the RNA has been determined, and is known to play an important role in regulating translation. Paired regions of the genome have a higher G+C content than unpaired regions. It has been suggested that this reflects selection for high G+C content to encourage pairing, but a re-analysis of the data together with computer simulation suggest that it is an automatic consequence in any RNA sequence of the way it folds up to minimise its free energy. It has also been suggested that the three registers in which pairing can occur in a coding region are used differentially to optimise the use of the redundancy of the genetic code, but re-analysis of the data shows only weak statistical support for this hypothesis.

Base Composition↗

PubMed2022

Current advances in gene therapy of mitochondrial diseases.

Mitochondrial diseases (MD) are a heterogeneous group of multisystem disorders involving metabolic errors. MD are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystem dysfunction with different clinical courses. Most primary MD are autosomal recessive but maternal inheritance (from mtDNA), autosomal dominant, and X-linked inheritance is also known. Mitochondria are unique energy-generating cellular organelles designed to survive and contain their own unique genetic coding material, a circular mtDNA fragment of approximately 16,000 base pairs. The mitochondrial genetic system incorporates closely interacting bi-genomic factors encoded by the nuclear and mitochondrial genomes. Understanding the dynamics of mitochondrial genetics supporting mitochondrial biogenesis is especially important for the development of strategies for the treatment of rare and difficult-to-diagnose diseases. Gene therapy is one of the methods for correcting mitochondrial disorders.

Humans↗

PubMed2005

Choosing appropriate substitution models for the phylogenetic analysis of protein-coding sequences.

Although phylogenetic inference of protein-coding sequences continues to dominate the literature, few analyses incorporate evolutionary models that consider the genetic code. This problem is exacerbated by the exclusion of codon-based models from commonly employed model selection techniques, presumably due to the computational cost associated with codon models. We investigated an efficient alternative to standard nucleotide substitution models, in which codon position (CP) is incorporated into the model. We determined the most appropriate model for alignments of 177 RNA virus genes and 106 yeast genes, using 11 substitution models including one codon model and four CP models. The majority of analyzed gene alignments are best described by CP substitution models, rather than by standard nucleotide models, and without the computational cost of full codon models. These results have significant implications for phylogenetic inference of coding sequences as they make it clear that substitution models incorporating CPs not only are a computationally realistic alternative to standard models but may also frequently be statistically superior.

Classification↗

PubMed1999

The nonribosomal code.

How genes are expressed and translated into proteins (using mRNA, codons and tRNAs as adaptor molecules) forms the basis of the 'genetic code'. Many peptides are synthesized nonribosomally, however, by large protein complexes that also serve as templates. Recent advances have shed light on what the nonribosomal code is and how it can be read.

Acylation↗

PubMed1999

Linear DNA plasmid pPK2 of Pichia kluyveri: distinction between cytoplasmic and mitochondrial linear plasmids in yeasts.

The linear plasmids frequently found in plants and filamentous fungi are associated with mitochondria or chloroplasts. In contrast, all the linear plasmids known in yeasts are cytoplasmic elements. From a strain of the yeast Pichia kluyveri, we have isolated a new linear plasmid, pPK2, which was found to be associated with mitochondria. This 7.1 kilobase pairs-long DNA contained only two genes, which code for DNA and RNA polymerases, as judged from their nucleotide sequences translated by a mitochondrial genetic code. When we examined several recently isolated yeast plasmids for their subcellular localization, we found that two linear plasmids, pPH1 from Pichia heedii, as well as pPK1 from another strain of P. kluyveri, were also localized in mitochondria. These plasmids are the first examples of mitochondria-associated linear plasmids in yeast. All other linear plasmids we examined were of cytoplasmic origin. Whilst the cytoplasmic type linear plasmids were efficiently eliminated by ultraviolet irradiation of host cells, the mitochondria-associated plasmids were highly resistant. The mitochondrial pPK2 plasmid was rapidly lost by treatment of the host cells with ethidum bromide.

Amino Acid Sequence↗

PubMed1996

[Identification and characterization of new and unknown coronaviruses using RT-PCR and degenerate primers].

A modified method of the reverse transcription followed by polymerase chain reaction (RT-PCR) was developed in order to examine the genome of a recently discovered virus, the porcine epidemic diarrhoea virus (PEDV), which resembled morphologically the coronaviruses. The published sequences of the genomes of various coronaviruses were compared. On the level of the amino acid sequence, conserved regions, common to all coronaviruses, were found in the gene encoding the nonstructural protein 1b as well as in the genes coding for the major structural proteins (S, M, and N). Due to the degeneration of the genetic code, some amino acids may be encoded by different nucleotide triplets. In order to compensate for this degeneration, mixtures of primers were synthesized, containing a variety of nucleotide sequences which together represented all possible codons for the conserved amino acid sequences. This method allowed to amplify and clone approximately 4000 base pairs of the genome of PEDV. An analysis of the genomic sequences revealed that PEDV holds an interesting intermediate position between human coronavirus 229E and Transmissible Gastroenteritis virus. We postulate that the method presented in this contribution may be useful to study and characterize other unknown viruses, especially viruses for which no cell cultures for propagation are available.

Amino Acid Sequence↗

PubMed1999

Molecular Medicine and Molecular Pathology for Haematologists: I. Gene Speak made Easy: An Overview of Genes and Gene Expression.

Molecular Medicine and Molecular Pathology are integral parts of Haematology as we enter the new millennium. Their origins can be linked to fundamental developments in the basic sciences, particularly genetics, chemistry and biochemistry. The structure of DNA and the genetic code that it encrypts are the critical starting points to our understanding of these new disciplines. The genetic alphabet is a simple one, consisting of just 4 letters, buts its influence is crucial to human development and differentiation. The concept of a gene is not a new one but the Human Genome Project (a joint world-wide effort to characterise our entire genetic make-up) is providing an invaluable understanding of how genes function in normal cellular processes and pinpointing how disruption of these processes can lead to disease. Transcription and translation are the key events by which our genotype is converted to our phenotype (via a messenger RNA intermediate), producing the myriad proteins and enzymes which populate the cellular factory of our body. Unlike the bacterial or prokaryotic genome, the human genome contains a large amount of non coding DNA (less than 1% of our genome codes for proteins), and our genes are interrupted, with the coding regions or exons separated by non coding introns. Precise removal of the intronic material after transcription (though a process called splicing) is critical for efficient translation to occur. Incorrect splicing can lead to the generation of mutant proteins, which can have a dilaterious effect on the phenotype of the individual. Thus the 100,000-200,000 genes which are present in each cell in our body have a defined control mechanism permitting efficient and appropriate expression of proteins and enzymes and yet a single base change in just one of those genes can lead to diseases such as haemophilia or fanconis anaemia.

Journal Article↗