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PubMed1998

The Saccharomyces cerevisiae MLH3 gene functions in MSH3-dependent suppression of frameshift mutations.

The Saccharomyces cerevisiae genome encodes four MutL homologs. Of these, MLH1 and PMS1 are known to act in the MSH2-dependent pathway that repairs DNA mismatches. We have investigated the role of MLH3 in mismatch repair. Mutations in MLH3 increased the rate of reversion of the hom3-10 allele by increasing the rate of deletion of a single T in a run of 7 Ts. Combination of mutations in MLH3 and MSH6 caused a synergistic increase in the hom3-10 reversion rate, whereas the hom3-10 reversion rate in an mlh3 msh3 double mutant was the same as in the respective single mutants. Similar results were observed when the accumulation of mutations at frameshift hot spots in the LYS2 gene was analyzed, although mutation of MLH3 did not cause the same extent of affect at every LYS2 frameshift hot spot. MLH3 interacted with MLH1 in a two-hybrid system. These data are consistent with the idea that a proportion of the repair of specific insertion/deletion mispairs by the MSH3-dependent mismatch repair pathway uses a heterodimeric MLH1-MLH3 complex in place of the MLH1-PMS1 complex.

Base Sequence↗
PubMed1981

Neutralizing antibody spectrum determines the antigenic profiles of emerging mutants of visna virus.

The visna viruses are antigenically related nononcogenic retroviruses of sheep. The original strain was isolated from the brain of a paralyzed sheep in Iceland during the 1940s. The prototype strains has been passed serially in sheep and has undergone progressive antigenic change. Previous reports have shown that such antigenic changes in visna virus can be reproduced in infected cell cultures treated with neutralizing antibody. We now show that the antigenic profiles of the emerging mutants directly reflect the nature of the selecting antibody. Mutants with minor antigenic changes were selected by "early" sera which had a limited neutralization range. Mutants with greater antigenic changes were selected by "late" sera with a wide neutralization range. Mutants selected by early sera emerged rapidly and consistently in cultures, and these were antigenically very similar to one another. Mutants rarely emerged in cultures treated with late sera, but these viruses showed major antigenic changes. The data suggest that the evolution of antigenic mutants of visna virus progresses by a series of minor mutations which accumulate under the selective pressure of antibody.

Animals↗
PubMed2004

TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer.

Among genetic alterations, the activation of proto-oncogenes and inactivation of tumour suppressor genes in affected cells are considered to be the core molecular events that provide a selective growth advantage and clonal expansion during the multistep process of carcinogenesis. The TP53 tumour suppressor gene is mutated in about half of all human cancer cases. The p53 protein modulates multiple cellular functions, such as gene transcription, DNA synthesis and repair, cell cycle arrest, senescence and apoptosis. Mutations in the TP53 gene can abrogate these functions, leading to genetic instability and progression to cancer. The molecular archaeology of the TP53 mutation spectrum generates hypotheses concerning the etiology and molecular pathogenesis of each type of cancer. The spectrum of somatic mutations in the TP53 gene, of which 75% are missense mutations, implicates environmental carcinogens and endogenous processes in the etiology of human cancer. The presence of a characteristic TP53 mutation can also manifest a molecular link between exposure to a particular carcinogen and a specific type of human cancer, e.g. exposure to aflatoxin B1 (AFB1) and codon 249 mutations in hepatocellular carcinoma; exposure to ultraviolet (UV) light and C:C-->T:T tandem mutations in skin cancer; and cigarette smoking and the prevalence of G-->T transversions in lung cancer. Although exogenous carcinogens have been shown to target p53 selectively, evidence supporting the endogenous insult of TP53 from oxyradicals and nitrogen-oxyradicals is also accumulating. TP53 mutations can be a biomarker of carcinogen effect. Determining the characteristic TP53 mutation load in non-tumorous tissue, using a highly sensitive mutation assay, can indicate exposure to a specific carcinogen and may also help in identifying individuals at an increased risk of cancer.

Animals↗
PubMed1995

Immunoglobulin variable gene analysis of human autoantibodies reveals antigen-driven immune response to glutamate decarboxylase in type 1 diabetes mellitus.

Insulin-dependent (type 1) diabetes mellitus is an organ-specific autoimmune disease frequently associated with an islet-specific humoral autoimmune response. The role of islet cell autoantibodies in the disease process is unclear; in particular, it is not known whether they are a non-specific side effect of islet cell destruction or play a role in the autoimmune network leading to type 1 diabetes. Here we report the immunoglobulin gene usage and somatic mutation rates of a panel of seven human monoclonal islet cell autoantibodies (MICA 1-7) directed towards the major islet cell autoantigen glutamate decarboxylase (GAD). These autoantibodies were produced from cells from two patients with newly diagnosed type 1 diabetes. VH1, VH4 and V lambda 2 gene segments were frequently used in the MICA, but no correlation between V gene usage and epitope recognition was found. The nonrandom ratio of replacement versus silent mutations in the variable gene region, an accumulation of replacement mutations in the complementarity determining regions, which confer antigen binding, and the high relative avidity for GAD observed for MICA 1, 3, 4, and 6, suggested that the immune response to GAD is driven by the antigen. In contrast, MICA 2, 5, and 7, revealing a lower affinity for antigen, have accumulated a large number of silent mutations. These latter antibodies may, therefore, be characteristic for later stages of the chronic autoimmune disease. Our results argue in favor of an antigen-driven autoantibody response to islets in human type 1 diabetes. They suggest that GAD is an important target of autoimmunity associated with type 1 diabetes.

Amino Acid Sequence↗
PubMed1984

A nonpolymorphic class I gene in the murine major histocompatibility complex.

DNA sequence analysis of a class I gene (Q10), which maps to the Qa2,3 locus in the C57BL/10 (H-2b haplotype) mouse, reveals that it is almost identical to a cDNA clone (pH16) isolated from a SWR/J (H-2q haplotype) mouse liver cDNA library. Exon 5, in particular, has an unusual structure such that a polypeptide product is unlikely to be anchored in the cell membrane. Our findings suggest that the two sequences are derived from allelic class I genes, which are nonpolymorphic, in contrast to H-2K allelic sequences from the same mice, and they may encode liver-specific polypeptides of unknown function. Our previous studies indicate that the Q10 gene is a potential donor gene for the generation of mutations at the H-2K locus by inter-gene transfer of genetic information. Thus the lack of polymorphism in class I genes at the Q10 locus implies either that they are not recipients for such exchanges or that selective pressure prevents the accumulation of mutations in genes at this locus.

Alleles↗
PubMed2001

Tumor suppressor genes: at the crossroads of molecular carcinogenesis, molecular epidemiology and human risk assessment.

The p53 tumor suppressor gene is mutated in about half of all human cancer cases. The p53 protein modulates multiple cellular functions, such as gene transcription, DNA synthesis and repair, cell cycle arrest, senescence, and apoptosis. Mutations in the p53 gene can abrogate these functions and may lead to genetic instability and progress to cancer. The molecular archeology of the p53 mutation spectrum generates hypotheses concerning the etiology and molecular pathogenesis of cancer. The spectrum of somatic mutations in the p53 gene implicates environmental carcinogens and endogenous processes in the etiology of human cancer. The presence of a characteristic p53 mutation also can manifest a molecular link between exposure to a particular carcinogen and a specific type of human cancer, e.g. aflatoxin B1 (AFB1) exposure and codon 249ser mutations in hepatocellular carcinoma, ultraviolet (UV) exposure and CC to TT tandem mutations in skin cancer, and cigarette smoke and the prevalence of G to T transversions in lung cancer. Although several different exogenous carcinogens have been shown to selectively target p53, evidence supporting the endogenous insult of p53 from oxyradical and nitrogen-oxyradicals is accumulating. p53 mutations can be a biomarker of carcinogen effect. Determining the characteristic p53 mutation load in nontumorous tissue, with a highly sensitive mutation assay, can indicate a specific carcinogen exposure and also may help in identifying individuals at an increased risk of cancer.

Carcinogens↗
PubMed1998

VH usage and somatic hypermutation in peripheral blood B cells of patients with rheumatoid arthritis (RA).

The human antibody repertoire has been demonstrated to have a marked V-gene-dependent bias that is conserved between individuals. In RA patients, certain heavy chain V genes (VH) have been found to be preferentially used for encoding autoantibodies. To determine if such preferential use of VH genes in autoantibodies is associated with a general distortion of the V gene repertoire in RA patients, the VH composition of peripheral blood B cells was analysed among four RA patients and four age- and sex-matched healthy controls. Usage of individual VH genes (eight VH3 and three VH4 genes tested by hybridization with a set of gene-specific oligonucleotide probes) was highly biased among RA patients, but no evidence of a distortion in the bias was observed compared with healthy controls. However, the occurrence of somatic mutations in these VH genes (estimated by differential hybridization with motif-specific oligonucleotide probes targeted to CDR and FR of the tested genes, and by DNA sequence analysis) was strikingly different between patients and healthy subjects. The number of VH3 rearrangements that had accumulated somatic mutations and the number of mutations per rearrangement were significantly elevated in three of the four RA patients. A slight but not significant elevation in mutations among rearranged VH4 genes was also observed in these patients. These data suggest that although usage of individual VH genes among peripheral blood B cells is not affected by the disease, the autoimmune process may involve a significant fraction of the B cell compartment.

Antibodies↗
PubMed1992

[Biology of small-cell bronchogenic carcinoma: recent advances].

In the last ten years considerable progress has been made in small-cell lung carcinoma (SCLC) biology, along with the technical progress made in molecular biology. This progress now allows us to propose a model for the genesis and the development of this type of tumor. Tobacco, the principal causal factor plays a dual role. In bringing about secretion of growth factors by the bronchial epithelia, usually involved in the normal development of lungs, and by functioning autocrinally and paracrinally, it facilitates the occurrence of mitotic mutations. Without directly contributing to cellular transformation, this autocrine functioning also gives a selective advantage to cells going through transformation or immortalization. The procarcinogenic or carcinogenic agents contained in tobacco smoke, whose level of production could be genetically determined, would also contribute to the accumulation of mutations affecting both suppressor genes and oncogenes. Two tumour suppressor genes have been identified: RB1 and P53. At least one other putative tumour suppressor gene has constantly been implied. It lies on the short arm of chromosome 3. There could also be the possibility of detecting subjects susceptible to developing an SCLC, a functional hemizygote still needing evaluation. The activated oncogenes principally belongs to the myc family. Their activation could correspond with the appearance of cellular clones having aggressive behavior independent of growth factors, chemoresistant and more metastatic. SCLC may be distinguished from other malignant lung tumors by a fairly characteristic pattern consisting of the loss of suppressor genes and the activation of oncogenes. The links between the neuroendocrine properties of this type of tumor and its characteristic description are being clarified and will contribute to a better understanding of the relationship between the different types of lung tumors. From this biologic knowledge follow several therapeutic applications under investigation (blocking autocrine loop through anti-GRP antibodies), as well as potential applications (concerning the products of suppressor genes) and possible applications such as prevention oriented towards detection of high-risk subjects.

Carcinoma, Bronchogenic↗
PubMedDate not supplied

Racial comparison of p53 alterations in breast cancer: difference in prognostic value.

A significant difference in breast cancer survival between blacks and whites has been observed in the United States. Biological variation between races has been suggested to explain the difference. We investigated the difference by comparing the prognostic value of p53 alterations (mutations and protein accumulation) between black and white breast cancer patients. Black, but not white, patients with p53 mutations had a significantly poorer survival than those without p53 mutations (p < 0.05). In contrast, white, but not black, patients having tumors with p53 protein accumulation tended to have a poorer survival than those without accumulation of p53 protein (p = 0.058). Among patients who died of breast cancer, blacks were often to have p53 mutations without protein accumulation, and whites frequently had p53 protein accumulation without mutations. The racial disparities in the associations of p53 alterations with breast cancer survival could have clinical implications in terms of treatment management.

Black People↗
PubMed2000

Tissue mitochondrial DNA changes. A stochastic system.

Several lines of evidence support the view that the bioenergetic function of the mitochondria in postmitotic tissue deteriorates during normal aging. Skeletal muscle is one such tissue that undergoes age-related fiber loss and atrophy and an age-associated rise in the number of cytochrome c oxidase (COX) deficient fibers. With such metabolic pressure placed on skeletal muscle it would be an obvious advantage to supplement the cellular requirement for energy by up-regulating glycolysis, and alternative pathway for energy synthesis. Analysis of rat skeletal muscle utilizing antibodies directed against key enzymes involved in glycolysis has provided evidence of an age-associated increase in the enzymes involved in glycolysis. Fructose-6-phosphate kinase, aldolase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate kinase protein levels appeared to increase in the soleus, gracilis, and quadriceps muscle from aged rats. The increase in the level of these proteins appeared to correlate to a corresponding decrease in the amount of cytochrome c oxidase protein measured in the same tissue. Together these results are interpreted to represent a general upregulation of glycolysis that occurs in response to the age-associated decrease in mitochondrial energy capacity. Mitochondrial DNA (mtDNA) damage and mutations may accumulate with advancing age until they reach a threshold level were they impinge on the bioenergy capacity of the cell or tissue. Evidence indicates that mtDNA from the skeletal muscle of both aged rats and humans not only undergoes changes at the nucleotide sequence level (mutations and DNA damage), but also undergoes modifications at the tertiary level to generate unique age-related conformational mtDNA species. One particular age-related conformational form was only detected in aged rat tissues with high demands on respiration, specifically in heart, kidney, soleus muscle, and, to a lesser extent, the quadriceps muscle. The age-related form was not detected in gracilis muscle which is predominantly dependent upon glycolysis with regard to its energy requirements. Finally, a comprehensive hypothesis is presented that features the stochastic nature of the mitochondrial system. The basis of the hypothesis is that a dynamic relationship exists between endogenous mutagen production, DNA repair, mtDNA turnover, and nuclear control of mtDNA copy number and that age-associated changes in the dynamics of this relationship lead to a loss of functional full-length mtDNA that eventually leads to bioenergy decline.

Aging↗
PubMed2005

The severity of roX1 mutations is predicted by MSL localization on the X chromosome.

Dosage compensation equalizes the expression of sex-linked genes between males and females. Most genes on the X chromosome of male Drosophila are transcribed at an increased level, contributing to compensation. The roX1 and roX2 genes produce non-coding transcripts that localize along the X-chromosome of male flies. Although lacking sequence similarity, they are necessary but redundant components of a system that up-regulates gene expression. Simultaneous mutation of both roX genes disrupts the X-limited distribution of proteins that modify chromatin to enhance gene expression. We have generated and characterized loss of function roX1 alleles that display a continuum of activity. Those that support intermediate male survival have strikingly reduced RNA accumulation, while alleles with minor contributions to male viability typically lack detectable transcript accumulation. Severely mutated roX1 alleles retain some ability to direct modifying proteins to the X chromosome. This ability predicts the level of male survival that each allele supports. This points to a peripheral or transient role for roX in the RNA and protein complex that binds to and regulates the X chromosome.

Alleles↗
PubMed2002

Detection of anti-p53 antibodies by ELISA using p53 synthetic or phage-displayed peptides.

Anti-p53 antibodies have been detected in the sera of patients with various types of cancers. In this report, we describe the development of a new ELISA aimed at detecting anti-p53 antibodies using two peptides belonging to immunodominant epitopes of the p53 N-terminal region. We first tested the reactivity of the sera by an indirect ELISA using the peptides as a capture system. Then, the specificity of the reaction was confirmed by an inhibition assay. Two systems of peptide presentation, phage display and the streptavidin/biotin system, were evaluated. Using a panel of sera from cancer patients, both systems were found to be equally reliable, demonstrating that both peptide-based ELISAs can be used for the specific detection of anti-p53 antibodies. The presence of anti-p53 antibodies was associated with p53 alteration whether it be mutation or accumulation.

Antibodies, Neoplasm↗
PubMed1999

Genomic nucleotide sequence of a foot-and-mouth disease virus clone and its persistent derivatives. Implications for the evolution of viral quasispecies during a persistent infection.

The consensus nucleotide sequence of the entire genome of foot-and-mouth disease virus (FMDV) (biological clone C-S8c1) has been completed, and compared with that of two persistent derivatives R99 and R146, rescued after 99 and 146 passages of the carrier BHK-21 cells. Consensus sequences were determined directly from supernatants of persistently infected cells, without intervening cytolytic amplification of the viruses. These genomic sequences have also been compared with that of FMDV R100, a virus that was also rescued from persistently infected cells, but that was subjected to cytolytic amplification prior to sequencing. Mutation frequencies for R99 and R146 relative to C-S8c1 were in the range of 2.8x10(-3) to 7.7x10(-3) substitutions per nucleotide for the 5'-UTR and the L-, P1-, P2- and P3-coding regions. No mutations were fixed in the polymerase (3D)-coding region. Striking contrasts were noted regarding the distribution of mutation types along the persistent genomes, notably the complete absence of transversion mutations within the 5'-UTR, compared with 53% transversions in the L- and P1-coding regions. The sequencing results presented here, combined with previous sequences of FMDV C-S8c1 genomes at the onset of persistence, provide evidence of sequence fluctuations with a non-linear accumulation of mutations during prolonged persistence, a hallmark of quasispecies dynamics.

3' Untranslated Regions↗
PubMed2002

Breaking symmetry: mutations engineered into R67 dihydrofolate reductase, a D2 symmetric homotetramer possessing a single active site pore.

R67 dihydrofolate reductase (DHFR) is an enzyme, encoded by an R-plasmid, that confers resistance to the antibacterial agent trimethoprim. This homotetramer possesses a single active site pore and exact 222 symmetry. The symmetry imposes constraints on the ability of the enzyme to optimize binding of the substrate, dihydrofolate (DHF), and the cofactor, NADPH, resulting in a "one site fits both ligands" approach. This approach allows formation of either a NADPH.NADPH, dihydrofolate.dihydrofolate, or NADPH.dihydrofolate complex. The first two complexes are nonproductive, while the third is the productive catalytic species. To break the symmetry of the active site, a tandem array of four R67 DHFR genes has been linked in frame, allowing individual manipulation of each gene copy. Various numbers and combinations of asymmetric Q67H mutations have been engineered into the tandem gene array. The Q67H mutation was chosen for investigation as it was previously found to tighten binding to both dihydrofolate and NADPH by approximately 100-fold in homotetrameric R67 DHFR [Park, H., Bradrick, T. D., and Howell, E. E. (1997) Protein Eng. 10, 1415-1424]. Nonadditive effects on ligand binding are observed when one to four mutations are inserted, indicating either conformational changes in the protein or different cooperativity patterns in the ligand-ligand interactions. From steady state kinetics, addition of Q67H mutations does not drastically affect formation of the NADPH.dihydrofolate complex; however, a large energy difference between the productive and nonproductive complexes is no longer maintained. A role for Q67 in discriminating between these various states is proposed. Since theories of protein evolution suggest gene duplication followed by accumulation of mutations can lead to divergence of activity, this study is a first step toward asking if introduction of asymmetric mutations in the quadrupled R67 DHFR gene can lead to optimization of ligand binding sites.

Amino Acid Substitution↗
PubMed2000

Respiratory chain complex I is essential for sexual development in neurospora and binding of iron sulfur clusters are required for enzyme assembly.

We have cloned and disrupted in vivo, by repeat-induced point mutations, the nuclear gene coding for an iron sulfur subunit of complex I from Neurospora crassa, homologue of the mammalian TYKY protein. Analysis of the obtained mutant nuo21.3c revealed that complex I fails to assemble. The peripheral arm of the enzyme is disrupted while its membrane arm accumulates. Furthermore, mutated 21.3c-kD proteins, in which selected cysteine residues were substituted with alanines or serines, were expressed in mutant nuo21. 3c. The phenotypes of these strains regarding the formation of complex I are similar to that of the original mutant, indicating that binding of iron sulfur centers to protein subunits is a prerequisite for complex I assembly. Homozygous crosses of nuo21.3c strain, and of other complex I mutants, are unable to complete sexual development. The crosses are blocked at an early developmental stage, before fusion of the nuclei of opposite mating types. This phenotype can be rescued only by transformation with the intact gene. Our results suggest that this might be due to the compromised capacity of complex I-defective strains in energy production.

Animals↗
PubMed1998

The dynamics of early intestinal tumour proliferation: to be or not to be.

New data and approaches bring novel perspectives and possibilities to old problems. The speculation of this chapter attempts to merge the puzzling MS data observed in human tumours (Figs. 3 and 4B) within a multistep tumour progression model. Clearly the current models are gross simplifications and other, more sophisticated models may better account for the distribution of MS alleles found in human tumours. The findings and the data are also limited to MMR deficient tumours, and studies in non-mutator phenotype tumours may be more difficult since fewer polymorphisms will arise during progression. The current model, however, precisely defines proliferation and clearly delineates two very distinct patterns. Further studies using MS loci in MMR deficient tumours will allow fairer tests of alternative pathways (Fig. 4C) to cancer. Evolution proceeding in occult progenitor populations allows mutations to accumulate throughout life and not just in the last decades after polyps appear.

Animals↗
PubMed2005

Argonaute protein PIWI controls mobilization of retrotransposons in the Drosophila male germline.

Proteins of the Argonaute family have been identified as key components of RNA interference (RNAi) pathway. RNAi-related mechanisms are implicated in the regulation of gene expression and repression of transposable elements in eukaryotes. The piwi gene encoding protein of the Drosophila Argonaute family was shown to be required for the germ stem cells maintenance. Here, we show that piwi is involved in silencing of LTR retrotransposons in testes. piwi mutations led to derepression of endogenous retrotransposon copia as well as to upregulation of the reporter gene driven by copia LTR. piwi mutation causes accumulation of retrotransposon mdg1 transcripts at the apical tip of testes, including germinal proliferative center where PIWI protein was shown to be expressed. We applied inverse PCR approach to detect the newly arisen insertions of the mdg1 retrotransposon in the progeny of individual piwi mutant males. Owing to piwi mutation a high rate of mdg1 transpositions was revealed. Thus, piwi is involved in the silencing of retrotransposons in the precursors of male gametes. Our results provide the first evidence that protein of the Argonaute family prevents retrotranspositions. It is supposed that the disturbance of RNA silencing system in germinal cells might cause transposition burst.

Animals↗
PubMed1995

Splenic lymphoma with villous lymphocytes involves B cells with extensively mutated Ig heavy chain variable region genes.

Splenic lymphoma with villous lymphocytes (SLVL) is a recently defined subgroup of chronic B-cell lymphoproliferative diseases. The characteristic morphology of the tumor cells, together with phenotypic and cytogenetic findings, indicate that it is a distinct entity, but the nature of the cell or origin and its relationship to other low-grade lymphomas is unclear. For B-cell tumors, analysis of the variable region heavy chain (VH) genes used to encode the clonal Ig has shown marked differences between histologic categories, both in gene usage and extent of somatic mutation. An investigation of VH genes used in five typical cases of SLVL has shown somatic hypermutation from germline sequences in all cases, indicating that the cell of origin has been exposed to the hypermutation mechanism. However, no clonal heterogeneity was detectable, demonstrating that the tumor cell does not accumulate further mutations. These characteristics are similar to those found in mature postfollicular B cells, such as plasma cells. The distribution of mutations leading to replacement amino acids differed among the cases, with three of five cases showing clear evidence for antigen selection.

Aged↗