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PubMed2004

Dominant effects of an Msh6 missense mutation on DNA repair and cancer susceptibility.

Mutations in DNA mismatch repair (MMR) genes cause hereditary nonpolyposis colorectal cancer (HNPCC), and MMR defects are associated with a significant proportion of sporadic cancers. MMR maintains genome stability and suppresses tumor formation by preventing the accumulation of mutations and by mediating an apoptotic response to DNA damage. We describe the analysis of a dominant MSH6 missense mutation in yeast and mice that causes loss of DNA repair function while having no effect on the apoptotic response to DNA damaging agents. Our results demonstrate that MSH6 missense mutations can effectively separate the two functions, and that increased mutation rates associated with the loss of DNA repair are sufficient to drive tumorigenesis in MMR-defective tumors.

Animals↗
PubMed2002

Large genome rearrangements as a primary cause of aging.

In his introductory chapter of the Mutation Research special issue on 'Genetic Instability and Aging', the late Bernard Strehler provided some historical perspectives on the long-standing hypothesis that aging is primarily caused by changes in the genome of somatic cells (Strehler, 1995, Mutat. Res. 338 (1995) 3). Based on his own findings of a loss of ribosomal RNA gene copies in postmitotic tissues of dogs as well as humans during aging, his main conclusion was that deletional mutations are more likely than point mutations to be a main causal factor in aging. To directly assess the levels of different types of spontaneous mutations in organs and tissues during aging, we have used a mouse model harboring a chromosomally integrated cluster of lacZ-containing plasmids that can be recovered and analyzed in Escherichia coli. Our results indicate the accumulation of mutations in some but not all organs of the mouse with significant differences in mutational spectra. In addition to point mutations, genome rearrangements involving up to 66 Mb of genomic DNA appeared to be a major component of the mutational spectra. Physical characterization of the breakpoints of such rearrangements indicated their possible origin by erroneous, non-homologous DNA double-strand break repair. Based on their increased occurrence during aging in some tissues and their often very large size, we have designed a model for an aging tissue in terms of a cellular mosaic with a gradual increase in genome rearrangements that leads to functional senescence, neoplastic transformation or death of individual cells by disrupting nuclear architecture and patterns of gene regulation.

Aging↗
PubMed1996

Mutator genes and mosaicism in colorectal cancer.

Recent studies have shed light on the role of defective DNA mismatch repair in human cancer. An elevated mutation rate associated with mismatch repair deficiency has been demonstrated in the germline and normal tissue from patients with hereditary non-polyposis colorectal cancer and transgenic animals respectively. Thus mismatch repair deficiency may permit the accumulation of mutations in cancer genes that do not confer growth advantage. This represents one potential mechanism for the induction of mutational mosaicism in humans.

Animals↗
PubMed2007

Characteristics, causes and evolutionary consequences of male-biased mutation.

Mutation has traditionally been considered a random process, but this paradigm is challenged by recent evidence of divergence rate heterogeneity in different genomic regions. One facet of mutation rate variation is the propensity for genetic change to correlate with the number of germ cell divisions, reflecting the replication-dependent origin of many mutations. Haldane was the first to connect this association of replication and mutation to the difference in the number of cell divisions in oogenesis (low) and spermatogenesis (usually high), and the resulting sex difference in the rate of mutation. The concept of male-biased mutation has been thoroughly analysed in recent years using an evolutionary approach, in which sequence divergence of autosomes and/or sex chromosomes are compared to allow inference about the relative contribution of mothers and fathers in the accumulation of mutations. For instance, assuming that a neutral sequence is analysed, that rate heterogeneity owing to other factors is cancelled out by the investigation of many loci and that the effect of ancestral polymorphism is properly taken into account, the male-to-female mutation rate ratio, alpham, can be solved from the observed difference in rate of X and Y chromosome divergence. The male mutation bias is positively correlated with the relative excess of cell divisions in the male compared to the female germ line, as evidenced by a generation time effect: in mammals, alpham is estimated at approximately 4-6 in primates, approximately 3 in carnivores and approximately 2 in small rodents. Another life-history correlate is sexual selection: when there is intense sperm competition among males, increased sperm production will be associated with a larger number of mitotic cell divisions in spermatogenesis and hence an increase in alpham. Male-biased mutation has implications for important aspects of evolutionary biology such as mate choice in relation to mutation load, sexual selection and the maintenance of genetic diversity despite strong directional selection, the tendency for a disproportionate large role of the X (Z) chromosome in post-zygotic isolation, and the evolution of sex.

Cell Division↗
PubMed1998

Allelic exchange at the endogenous genomic locus in Plasmodium falciparum proves the role of dihydropteroate synthase in sulfadoxine-resistant malaria.

We have exploited the recently developed ability to trans- fect the malaria parasite Plasmodium falciparum to investigate the role of polymorphisms in the enzyme dihydropteroate synthase (DHPS), identified in sulfadoxine-resistant field isolates. By using a truncated form of the dhps gene, specific mutations were introduced into the endogenous gene by allelic replacement such that they were under the control of the endogenous promoter. Using this approach a series of mutant dhps alleles that mirror P.falciparum variants found in field isolates were found to confer different levels of sulfadoxine resistance. This analysis shows that alteration of Ala437 to Gly (A437G) confers on the parasite a 5-fold increase in sulfadoxine resistance and addition of further mutations increases the level of resistance to 24-fold above that seen for the transfectant expressing the wild-type dhps allele. This indicates that resistance to high levels of sulfadoxine in P.falciparum has arisen by an accumulation of mutations and that Gly437 is a key residue, consistent with its occurrence in most dhps alleles from resistant isolates. These studies provide proof that the mechanism of resistance to sulfadoxine in P.falciparum involves mutations in the dhps gene and determines the relative contribution of these mutations to this phenotype.

Alleles↗
PubMed2026

Proteomic Analysis Identifies Potential Biomarkers of ELOC -Mutated Renal Cell Carcinoma.

ELOC -mutated renal cell carcinoma (RCC) is a rare tumor with only ∼40 cases reported to date; it shares a molecular background with clear cell RCC (ccRCC) in terms of hypoxia-inducible factor-alpha (HIF-α) protein accumulation. ELOC -mutated RCC is characterized by prominent leiomyomatous stromal growth and a more indolent clinical course compared with ccRCC. In our previous study, whole-genome sequencing of 102 ccRCC cases identified 5 cases of ELOC -mutated RCC. In the present study, we conducted proteomic and immunohistochemical analyses on up to 13 Japanese ELOC -mutated RCCs, including 8 previously reported cases, to elucidate its distinct molecular mechanisms and identify biomarkers that may be useful in distinguishing ELOC -mutated RCC from ccRCC. Proteomic profiling revealed that molecules, including cytokeratin 7, scinderin (SCIN), and sortilin 1 (SORT1), were significantly overexpressed in ELOC -mutated RCC compared with ccRCC. Notably, SCIN and SORT1 emerged as novel potential diagnostic biomarkers for distinguishing ELOC -mutated RCC from ccRCC. The analysis further suggested that ELOC -mutated RCC relies more on oxidative phosphorylation and less on glycolysis than ccRCC. This metabolic shift may be linked to the relative depletion of NAD+ due to the low expression of NAPRT and QPRT. In addition, we observed geographic variation in the disease frequency among different cohorts, with a higher frequency in Japan. Our findings provide novel insights into the pathogenesis of ELOC -mutated RCC and highlight SCIN and SORT1 as potential supportive biomarkers.

Humans↗
PubMed1975

Deoxyribonucleic acid-binding proteins in vegetative Bacillus subtilis: alterations caused by stage O sporulation mutations.

Deoxyribonucleic acid (DNA)-binding proteins have been compared between wild-type Bacillus subtilis and five sporulation mutants blocked at different stage O loci. Extracts from exponentially growing cells have been fractionated for proteins binding to single-stranded calf thymus DNA-cellulose and double-stranded B. subtilis DNA-cellulose. In nutrient broth, stage O mutations cause an accumulation of proteins with affinity for double-stranded DNA. Suppression of the mutation with extragenic suppressors relieves the accumulation. In minimal glucose medium, the stage O mutations also cause accumulation of proteins with affinity for double-stranded DNA, but the species accumulated are different from those of nutrient broth-grown cells. In neither case did stage O mutations affect proteins with affinity for single-stranded DNA. The results suggest that the products of stage O loci are functional and operative during vegetative growth.

Bacillus subtilis↗
PubMed2004

Activation-induced cytosine deaminase (AID) is actively exported out of the nucleus but retained by the induction of DNA breaks.

Activation-induced cytosine deaminase (AID) is a cytosine deaminase that is critical to immunoglobulin hypermutation, class switch recombination, and gene conversion. In the context of hypermutating B cells, AID deaminates cytosine in the DNA of immunoglobulin genes, leading to the accumulation of mutations in the variable regions. However, when AID is expressed ectopically, it is a generalized mutator of G:C base pairs. Therefore, we asked whether AID may be partially regulated by an active system of nuclear export. We found that removal of a highly conserved nuclear export signal in the C terminus of AID causes accumulation of AID in the nucleus. However, a putative nuclear localization signal in the N terminus does not appear to be functional. Finally, we found that agents that induce DNA breaks caused retention of AID in the nucleus, suggesting that DNA breaks or the repair patches initiated as a result are a substrate for AID binding.

Active Transport, Cell Nucleus↗
PubMed1998

Some, but not all, glycine substitution mutations in COL7A1 result in intracellular accumulation of collagen VII, loss of anchoring fibrils, and skin blistering.

COL7A1 gene mutations cause dystrophic epidermolysis bullosa, a skin blistering disorder. The phenotypes result from defects of collagen VII, the major component of the anchoring fibrils at the dermo-epidermal junction; however, the molecular mechanisms underlying the phenotypes remain elusive. We investigated naturally occurring COL7A1 mutations and showed that some, but not all, glycine substitutions in collagen VII interfered with biosynthesis of the protein in a dominant-negative manner. Three point mutations in exon 73 caused glycine substitutions G2006D, G2034R, and G2015E in the triple helical domain of collagen VII and interfered with its folding and secretion. Confocal laser scanning studies and semiquantitative immunoblotting determined that dystrophic epidermolysis bullosa keratinocytes retained up to 2.5-fold more procollagen VII within the rough endoplasmic reticulum than controls. Limited proteolytic digestions of mutant procollagen VII produced aberrant fragments and revealed reduced stability of the triple helix. In contrast, the glycine substitution G1519D in another segment of the triple helix affected neither procollagen VII secretion nor anchoring fibril function and remained phenotypically silent. These data demonstrate that collagen VII presents a remarkable exception among collagens in that not all glycine substitutions within the triple helix exert dominant-negative interference and that the biological consequences of the substitutions probably depend on their position within the triple helix.

Adult↗
PubMed1993

The Saccharomyces cerevisiae PRP21 gene product is an integral component of the prespliceosome.

In Saccharomyces cerevisiae, the prp21 mutation causes accumulation of unspliced pre-mRNA at the nonpermissive temperature. We have cloned the PRP21 gene by complementation of its temperature-sensitive phenotype and found it to be the same as SPP91, an extragenic suppressor of the prp9 mutation previously studied in vivo by Chapon and Legrain [Chapon, C. & Legrain, P. (1992) EMBO J. 11, 3279-3288]. We have analyzed the effects of the prp21 mutation on splicing in vitro and have found that PRP21 is a splicing factor required for prespliceosome assembly. We also have analyzed the interaction of PRP21 with splicing complexes using anti-PRP21 antibodies and found that the RNA components of the prespliceosome--U1 and U2 small nuclear RNA (snRNA) particles and pre-mRNA--are specifically coimmunoprecipitated under splicing conditions in the presence of 0.2 M KCl. At higher KCl concentrations, U1 snRNP dissociates from splicing complexes; nevertheless, U2 snRNA and pre-mRNA are still efficiently immunoprecipitated. Immunoprecipitation of both U1 and U2 snRNA as well as pre-mRNA is ATP-dependent and requires a pre-mRNA capable of supporting prespliceosome assembly. Analysis of the unbound complexes in native gels confirmed that prespliceosomes are specifically immunoprecipitated by anti-PRP21 antibodies. These results demonstrate that PRP21 is an integral component of the prespliceosome and establishes a stable interaction with U2 snRNP and/or pre-mRNA in that complex.

Cloning, Molecular↗
PubMed2005

Age related shift in the mutation spectra of germline and somatic NF2 mutations: hypothetical role of DNA repair mechanisms.

It has been suggested that somatic mutations that accumulate due to an age related decline in the efficiency of DNA repair mechanisms might contribute to the increased incidence of cancer in older people. However, there is little direct evidence for this phenomenon. The spectra of germline and somatic mutations can be compared in cancer genes that cause inherited tumour syndromes and sporadic tumours, respectively. In addition, mosaic patients reflect the nature of mutations that occur in early development. Hence, we hypothesised that the "temporal mutation record" of a human cancer gene might provide insight into mechanisms of mutagenesis in the germline, in early development, and in adulthood. We compared the ratio of frameshift to nonsense mutations in three diseases that are related to the NF2 tumour suppressor gene: classic neurofibromatosis 2 (NF2), caused by germline NF2 mutations; mosaic NF2; and unilateral sporadic vestibular schwannoma (USVS), caused by somatic NF2 inactivation. Nonsense mutations predominated in both classic and mosaic NF2, but the ratio of nonsense to frameshift mutations was reversed in USVS. Moreover, in USVS patients, the ratio of somatic frameshift to nonsense mutations increased significantly with increasing age at diagnosis. This pattern is consistent with an age related decline in the efficiency of DNA repair mechanisms. Similar studies for other familial cancer genes may provide further evidence for this hypothesis.

Age Factors↗
PubMed2004

The impact of the M184V substitution on drug resistance and viral fitness.

Treatment of HIV/AIDS with antiretroviral therapy can result in HIV-1 drug resistance, limiting its use. Resistance mutations arise prior to therapy due to errors in HIV-1 replication, and are also spread by sexual and other modes of transmission. However, it is also generally believed that resistance is due to multiple drug mutations to any single or combination of antiretroviral agents selected during viral replication in the presence of incompletely suppressive drug regimens. In the case of protease inhibitors and most nucleoside analog reverse transcriptase inhibitors, drug resistance is due to the accumulation of mutations in the HIV-1 protease and reverse transcriptase genes respectively. However, in the case of non-nucleoside reverse transcriptase inhibitors, a single primary drug mutation is usually sufficient to abrogate antiviral activity. This is also true of certain specific mutations, such as M184V in the reverse transcriptase enzyme, resulting in resistance to the nucleoside analog, lamivudine (Epivir, GlaxoSmithKline). However, it is thought that lamivudine may still contribute to the effectiveness of antiretroviral therapy, even after the appearance of the M184V mutation. M184V may affect sensitivity to other drugs, such as zidovudine (Retrovir, GlaxoSmithKline), in HIV-1 variants that already contain resistance mutations to zidovudine, during concomitant treatment with lamivudine. M184V also has a positive effect on HIV-1 RT fidelity, reducing spontaneous HIV mutagenesis. Processivity of the reverse transcriptase enzyme may be affected by mutations such as M184V, and this may be a major determinant of viral replication fitness.

Amino Acid Substitution↗
PubMed1994

The p53 gene and protein in human brain tumors.

p53 mutation is most likely an integral early step in the formation of a subset of human diffuse, fibrillary astrocytomas, but is not a frequent event in other studied brain tumors. In astrocytomas, p53 mutations are clustered in the conserved regions of the gene and are predominantly single base pair transitions, frequently at CpG dinucleotides. These mutations result in mutant or truncated p53 proteins that lack the transcriptional activating ability to induce G1 arrest, DNA repair, apoptosis or differentiation. On the other hand, some astrocytomas without p53 mutations may accumulate wild-type protein, perhaps as a physiological response to DNA damage or deregulated proliferation in the tumor cells. Finally, while data on the p53 gene and protein studies in human brain tumors are accumulating rapidly, the clinical significance of such data remains unclear.

Astrocytoma↗
PubMed2000

Ineffectiveness of topoisomerase mutations in mediating clinically significant fluoroquinolone resistance in Escherichia coli in the absence of the AcrAB efflux pump.

Fluoroquinolone-resistant mutants, selected from a wild-type Escherichia coli K-12 strain and its Mar mutant by exposure to increasing levels of ofloxacin on solid medium, were analyzed by Northern (RNA) blot analysis, sequencing, and radiolabelled ciprofloxacin accumulation studies. Mutations in the target gene gyrA (DNA gyrase), the regulatory gene marR, and additional, as yet unidentified genes (genes that probably affect efflux mediated by the multidrug efflux pump AcrAB) all contributed to fluoroquinolone resistance. Inactivation of the acrAB locus made all strains, including those with target gene mutations, hypersusceptible to fluoroquinolones and certain other unrelated drugs. These studies indicate that, in the absence of the AcrAB pump, gyrase mutations fail to produce clinically relevant levels of fluoroquinolone resistance.

Anti-Infective Agents↗
PubMed2001

Identification and characterization of mutations in the high growth vaccine strain of influenza virus.

X-31(H3N2) virus, which is a high yielding reassortant between A/PR/8/34(H1N1) and A/Aichi/68(H3N2), is currently used as a backbone strain for influenza vaccine production. The sequence of the current X-31 virus was determined from cloned cDNA of 6 internal RNA genes, and was compared with the original sequence of the A/PR/8/34 virus. 71 point mutations were accumulated in the six internal viral genes (PB2, PB1, PA, NP, M and NS). These nucleotide changes encode 23 amino acid substitutions in seven viral proteins (PB2, PB1, PA, M1, M2, NS1 and NS2). Among three polymerase genes, a significantly low mutation frequency was observed in PA gene as compared to PB2 and PB1. The mutation frequency at the nucleotide level was significantly low in NP gene without any amino acid substitution, being only about 20% of those observed in 5 other internal genes. The unequal distribution of mutations among different viral proteins may correlate with individual role of each protein in viral growth.

Amino Acid Substitution↗
PubMed1989

Evidence for increased in vivo mutation and somatic recombination in Bloom's syndrome.

The glycophorin A assay was used to estimate the frequency of mutations that accumulate in vivo in somatic cells of persons with Bloom's syndrome (BS). This assay measures the frequency in persons of blood type MN of variant erythrocytes that lack the expression of one allelic form of glycophorin A, presumably due to mutational or recombinational events in erythroid precursor cells. Samples of blood from persons with BS showed dramatic 50- to 100-fold increases in the frequency of variants of three types, those with a hemizygous phenotype, those with a homozygous phenotype, and those with what appears to be partial loss of the expression of one locus. The high frequency of homozygous variants, genetic evidence for altered allelic segregation of a specific biochemical locus, provides evidence for increased somatic crossing-over in vivo in BS. An increased generation of functional hemizygosity and homozygosity in their somatic cells may play an important role in the extreme cancer risk of persons with BS.

Adolescent↗
PubMed1999

Dynamics of rabies virus quasispecies during serial passages in heterologous hosts.

To understand the mutations and genetic rearrangements that allow rabies virus infections of new hosts and adaptation in nature, the quasispecies structure of the nucleoprotein and glycoprotein genes as well as two noncoding sequences of a rabies virus genome were determined. Gene sequences were obtained from the brain and from the salivary glands of the original host, a naturally infected European fox, and after serial passages in mice, dogs, cats and cell culture. A relative genetic stasis of the consensus sequences confirmed previous results about the stability of rabies virus. At the quasispecies level, the mutation frequency varies, in the following order: glycoprotein region (21.9 x 10(-4) mutations per bp), noncoding sequence nucleoprotein-phosphoprotein region (7.2-7.9 x 10(-4) mutations per bp) and nucleoprotein gene region (2.9-3.7 x 10(-4) mutations per bp). These frequencies varied according to the number, type of heterologous passages and the genomic region considered. The shape of the quasispecies structure was dramatically modified by passages in mice, in which the mutation frequencies increased by 12-31 x 10(-4) mutations per bp, depending on the region considered. Non-synonymous mutations were preponderant particularly in the glycoprotein gene, stressing the importance of positive selection in the maintenance and fixation of substitutions. Two mechanisms of genomic evolution of the rabies virus quasispecies, while adapting to environmental changes, have been identified: a limited accumulation of mutations with no replacement of the original master sequence and a less frequent but rapid selective overgrowth of favoured variants.

Animals↗
PubMed2003

Proanthocyanidin-accumulating cells in Arabidopsis testa: regulation of differentiation and role in seed development.

Anthocyanidin reductase encoded by the BANYULS (BAN) gene is the core enzyme in proanthocyanidin (PA) biosynthesis. Here, we analyzed the developmental mechanisms that regulate the spatiotemporal expression of BAN in the developing Arabidopsis seed coat. PA-accumulating cells were localized histochemically in the inner integument (seed body and micropyle) and pigment strand (chalaza). BAN promoter activity was detected specifically in these cells. Gain-of-function experiments showed that an 86-bp promoter fragment functioned as an enhancer specific for PA-accumulating cells. Mutations in regulatory genes of PA biosynthesis abolished BAN promoter activity (transparent testa2 [tt2], tt8, and transparent testa glabra1 [ttg1]), modified its spatial pattern (tt1 and tt16), or had no influence (ttg2), thus revealing complex regulatory interactions at several developmental levels. Genetic ablation of PA-accumulating cells targeted by the BAN promoter fused to BARNASE led to the formation of normal plants that produced viable yellow seeds. Importantly, these seeds had no obvious defects in endosperm and embryo development.

Arabidopsis↗