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PubMed2001

Stabilization of the MDM2 oncoprotein by mutant p53.

MDM2 is a short-lived protein that regulates p53 degradation. We report here that transient coexpression of MDM2 and several p53 hotspot mutants resulted in stabilization and increased expression of MDM2. Ectopic expression of the mutant p53(175H) allele by recombinant adenovirus infection or stable transfection also stabilized endogenous MDM2 in p53-null cells. A panel of human tumor cell lines expressing different endogenous mutant p53 alleles also contained stabilized nuclear MDM2 at elevated levels when compared with p53-null cells. MDM2 was present in complexes with mutant p53 in tumor cells, and stabilization of MDM2 required direct binding to mutant p53. These results reveal a novel property of mutant p53 and a unique feature of tumors with p53 missense mutations. Accumulation of stable MDM2 may contribute to tumorigenesis through its p53-independent transforming functions.

Humans↗
PubMed2006

Evidence that accumulation of mutants in a biofilm reflects natural selection rather than stress-induced adaptive mutation.

The accumulation of mutant genotypes within a biofilm evokes the controversy over whether the biofilm environment induces adaptive mutation or whether the accumulation can be explained by natural selection. A comparison of the virulence of two strains of the dental pathogen Streptococcus mutans showed that rats infected with one of the strains accumulated a high proportion (average, 22%) of organisms that had undergone a deletion between two contiguous and highly homologous genes. To determine if the accumulation of deletion mutants was due to selection or to an increased mutation rate, accumulations of deletion mutants within in vitro planktonic and biofilm cultures and within rats inoculated with various proportions of deletion organisms were quantified. We report here that natural selection was the primary force behind the accumulation of the deletion mutants.

Adaptation, Physiological↗
PubMed2001

Long-distance movement and replication maintenance functions correlate with silencing suppression activity of potyviral HC-Pro.

The tobacco etch potyviral protein, HC-Pro, is a multifunctional proteinase required for long-distance movement in plants and maintenance of genome replication at the single-cell level. It also functions in a counterdefensive capacity as a suppressor of posttranscriptional gene silencing (PTGS). To determine whether the requirements for HC-Pro during long distance movement and replication maintenance are due to the silencing suppressor function of the protein, a series of HC-Pro alanine scanning and other site-directed mutants were analyzed. Using a transient silencing suppression assay in Agrobacterium-injected leaf tissue, several suppression-defective mutants were identified. Each of six HC-Pro mutations, which were shown previously to confer long-distance movement and replication maintenance defects, conferred PTGS suppression defects. Interestingly, the genes encoding these defective HC-Pro derivatives were themselves susceptible targets of PTGS, resulting in low levels of mRNA and protein accumulation. Mutations that inactivated the proteinase domain active site had no effect on PTGS suppression function. The results are consistent with the hypothesis that the role of HC-Pro in long-distance movement and genome replication depends on PTGS suppression function and that this function is independent of HC-Pro proteolytic activity.

Alanine↗
PubMed2005

Accumulation of mitochondrial DNA deletions is age, tissue and folate-dependent in rats.

Folate is essential for the synthesis, repair and methylation of DNA. Folate depletion causes nuclear genetic and epigenetic aberrations in cell culture, rodents and humans. We hypothesized that folate depletion may also damage mitochondrial (Mt) DNA and induce large-scale deletions due to DNA breakage. MtDNA deletions and mutations accumulate during aging and tumorogenesis and may play causative roles in these processes. Weanling and adult (12 months) Sprague Dawley rats consumed folate deplete, replete and supplemented diets (0, 2 and 8 mg/kg folate, respectively) for 20 weeks. The presence of random and common (4.8 kb) MtDNA deletions was measured in colonic mucosa and liver. Six Mt genomes (<16 kb) harboring random deletions were detected in the liver (3.5-7.0 kb) and three in the colon (3.8-8 kb). Older rats had significantly more random hepatic MtDNA deletions than young rats (64 and 3.2% of samples, respectively, P<0.0001), while age had no effect on these deletions in the colon (3.1 and 7.7% in young and old, respectively). Folate intake had no effect on the frequency of random deletions in either tissue. There was no discrete effect of aging on the common 4.8 kb deletion in the liver or colon. However, in the liver of old rats, increasing amounts of dietary folate reduced the deletion frequency, with replete and supplemented rats having 2.2- and 3.2-fold less deletions than the depleted rats. Our results confirm that random MtDNA deletions accumulate with age in a tissue-specific fashion. Furthermore, in contrast to previous work, we report that the common 4.8 kb deletion was not modulated by age, but is reduced by folate supplementation in the liver of rats.

Age Factors↗
PubMed2002

[ Mutation of mtDNA and genetic background of hypertrophic cardiomyopathy].

The operation of the structural and functional units of the myocardial contractile apparatus relies on mutual myofilament movement, totally ATP dependent. As a consequence, cardiac action is integrally connected with the production of high energy ATP molecules, which are mainly synthesised in cellular mitochondrial structures. Mitochondrial dysfunction can lead to a reduced level of ATP, which is necessary to generate movement in the actino-myosin system. ATP insufficiencies may be a result of the genetic mitochondrial material (mtDNA) mutation, poorer expression of mitochondrial genes (at the transcription and/or translation stage), distorted import of proteins from the cytoplasm to the mitochondria or erroneous composition of mitochondrial breathing complexes. It has been proved that the efficacy of oxidative phosphorylation (mitochondrial ATP synthesis) is reduced with accumulated mutation of mitochondrial and/or nuclear DNA. The paper is a review of findings on the mutation of mitochondrial DNA discovered in patients with hypertrophy of the cardiac muscle. In many cases these changes accompany the mutations of the nuclear genes, but they may also be the only change discovered in the patient's genetic material.

Adenosine Triphosphate↗
PubMed2004

Alterations of DNA mismatch repair proteins and microsatellite instability levels in gastric cancer cell lines.

Alterations in DNA mismatch repair (MMR) proteins result in microsatellite instability (MSI), increased mutation accumulation at target genes and cancer development. About one-third of gastric cancers display high-level microsatellite instability (MSI-High) and low-level microsatellite instability (MSI-Low) is frequently detected. To determine whether variations in the levels of MMR proteins or mutations in the main DNA MMR genes are associated with MSI-Low and MSI-High in gastric cancer cell lines, the MSI status (MSI-High, MSI-Low or MS-Stable (MSS)) of 14 gastric cancer lines was determined using multiple clone analysis with a panel of five microsatellite markers. Protein levels of hMLH1, hMSH2, hMSH6, hPMS2 and hPMS1 were determined by Western blot. Sequence analysis of hMLH1 and hMSH2 was performed and the methylation status of the hMLH1 promoter was examined. The cell lines SNU1 and SNU638 showed MSI-High, decreased to essentially absent hMLH1 and hPMS2 and reduced hPMS1 and hMSH6 protein levels. The hMLH1 promoter region was hypermethylated in SNU638 cells. The MKN28, MKN87, KATOIII and SNU601 cell lines showed MSI-Low. The MMR protein levels of cells with MSI-Low status was similar to the levels detected in MSS cells. A marked decrease in the expression levels of MutL MMR proteins (hMLH1, hPMS2 and hPMS1) is associated with high levels of MSI mutations in gastric cancer cells. Gastric cancer cell lines with MSI-Low status do not show significant changes in the levels of the main DNA MMR proteins or mutations in the DNA mismatch repair genes hMSH2 and hMLH1. These well-characterized gastric cancer cell lines are a valuable resource to further our understanding of DNA MMR deficiency in cancer development, progression and prognosis.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Cumulative effects of spontaneous mutations for fitness in Caenorhabditis: role of genotype, environment and stress.

It is often assumed that the mutation rate is an evolutionarily optimized property of a taxon. The relevant mutation rate is for mutations that affect fitness, U, but the strength of selection on the mutation rate depends on the average effect of a mutation. Determination of U is complicated by the possibility that mutational effects depend on the particular environmental context in which the organism exists. It has been suggested that the effects of deleterious mutations are typically magnified in stressful environments, but most studies confound genotype with environment, so it is unclear to what extent environmental specificity of mutations is specific to a particular starting genotype. We report a study designed to separate effects of species, genotype, and environment on the degradation of fitness resulting from new mutations. Mutations accumulated for >200 generations at 20 degrees in two strains of two species of nematodes that differ in thermal sensitivity. Caenorhabditis briggsae and C. elegans have similar demography at 20 degrees, but C. elegans suffers markedly reduced fitness at 25 degrees. We find little evidence that mutational properties differ depending on environmental conditions and mutational correlations between environments are close to those expected if effects were identical in both environments.

Animals↗
PubMed2002

A test of evolutionary theories of aging.

Senescence is a nearly universal feature of multicellular organisms, and understanding why it occurs is a long-standing problem in biology. The two leading theories posit that aging is due to (i) pleiotropic genes with beneficial early-life effects but deleterious late-life effects ("antagonistic pleiotropy") or (ii) mutations with purely deleterious late-life effects ("mutation accumulation"). Previous attempts to distinguish these theories have been inconclusive because of a lack of unambiguous, contrasting predictions. We conducted experiments with Drosophila based on recent population-genetic models that yield contrasting predictions. Genetic variation and inbreeding effects increased dramatically with age, as predicted by the mutation theory. This increase occurs because genes with deleterious effects with a late age of onset are unopposed by natural selection. Our findings provide the strongest support yet for the mutation theory.

Aging↗
PubMed2000

Oxidative stress and aging in Caenorhabditis elegans.

Much attention has been focused on the hypothesis that oxidative damage plays in cellular and organismal aging. A mev-1 (kn1) mutant of Caenorhabditis elegans, isolated on the basis of its methyl viologen (paraquat) hypersensitivity, is also hypersensitive to elevated oxygen levels. Unlike the wild type, its life span decreases dramatically as oxygen concentrations are increased from 1% to 60%. Strains, which bear this mutation, accumulate fluorescent materials and protein carbonyl groups, markers of aging, at faster rates than the wild type. We have cloned mev-1 gene by transformation rescue and found that it is, in fact, the previously sequenced gene (cyt-1) that encodes succinate dehydrogenase cytochrome b. A missense mutation abolishes complex II activity in the mitochondrial membrane but not succinate dehydrogenase enzyme activity per se. These data suggest that CYT-1 directly participates in electron transport from FADH2 to coenzyme Q. Moreover, mutational inactivation of this process renders animals susceptible to oxidative stress and, as a result, leads to premature aging.

Aging↗
PubMed2003

Error thresholds and the constraints to RNA virus evolution.

RNA viruses are often thought of as possessing almost limitless adaptability as a result of their extreme mutation rates. However, high mutation rates also put a cap on the size of the viral genome by establishing an error threshold, beyond which lethal numbers of deleterious mutations accumulate. Herein, I argue that a lack of genomic space means that RNA viruses will be subject to important evolutionary constraints because specific sequences are required to encode multiple and often conflicting functions. Empirical evidence for these constraints, and how they limit viral adaptability, is now beginning to accumulate. Documenting the constraints to RNA virus evolution has important implications for predicting the emergence of new viruses and for improving therapeutic procedures.

Adaptation, Biological↗
PubMed1999

Long-term follow-up of chimpanzees inoculated with the first infectious clone for hepatitis C virus.

Two chimpanzees (Ch1535 and Ch1536) became infected with hepatitis C virus (HCV) following intrahepatic inoculation with RNA transcribed from a full-length cDNA clone of the virus. Both animals were persistently infected and have been followed for 60 weeks. They showed similar responses to infection, with transient liver enzyme elevations and liver inflammatory responses, which peaked at weeks 17 (Ch1535) and 12 (Ch1536) postinoculation (p.i.). Antibody responses to structural and nonstructural proteins were first detected at weeks 13 (Ch1535) and 10 (Ch1536) p.i. Serum RNA titers increased steadily during the first 10 to 13 weeks but decreased sharply in both animals following antibody and inflammatory responses. Despite direct evidence of humoral immune responses to multiple viral antigens, including hypervariable region 1 (HVR1), both animals remained chronically infected. Detailed sequence analysis of serum HCV RNA revealed no change in the majority HVR1 sequence in Ch1535 and a single-amino-acid mutation in Ch1536, with very little clonal variation in either animal. Full-length genome analysis at week 60 revealed several amino acid substitutions localized to antigens E1, E2, p7, NS3, and NS5. Of these, 55.6 and 40% were present as the majority sequence in serum RNA isolated at week 26 p.i. (Ch1535) and week 22 p.i. (Ch1536), respectively, and could represent immune escape mutations. Mutations accumulated at a rate of 1.57 x 10(-3) and 1.48 x 10(-3) nucleotide substitutions/site/year for Ch1535 and Ch1536, respectively. Taken together, these data indicate that establishment of a persistent HCV infection in these chimpanzees is not due to changes in HVR1; however, the possibility remains that mutations arising in other parts of the genome contributed to this persistence.

Amino Acid Sequence↗
PubMed2005

Laboratory-directed protein evolution.

Systematic approaches to directed evolution of proteins have been documented since the 1970s. The ability to recruit new protein functions arises from the considerable substrate ambiguity of many proteins. The substrate ambiguity of a protein can be interpreted as the evolutionary potential that allows a protein to acquire new specificities through mutation or to regain function via mutations that differ from the original protein sequence. All organisms have evolutionarily exploited this substrate ambiguity. When exploited in a laboratory under controlled mutagenesis and selection, it enables a protein to "evolve" in desired directions. One of the most effective strategies in directed protein evolution is to gradually accumulate mutations, either sequentially or by recombination, while applying selective pressure. This is typically achieved by the generation of libraries of mutants followed by efficient screening of these libraries for targeted functions and subsequent repetition of the process using improved mutants from the previous screening. Here we review some of the successful strategies in creating protein diversity and the more recent progress in directed protein evolution in a wide range of scientific disciplines and its impacts in chemical, pharmaceutical, and agricultural sciences.

DNA Shuffling↗
PubMed1998

Erythrocyte as a potential model for study of lifelong somatic mutations.

The detection and measurement of somatic cell mutation in vivo is an important subject of research for the assessment of human cancer risk induced by various environmental genotoxic factors. The possible mechanisms which influence the persistence of mutant cells of the hematoimmune system in the peripheral blood are presented. The erythroid system is a system which accumulates mutational lesions and so stably generates red blood cells with various phenotypic changes.

Environmental Pollution↗
PubMed1986

Intragenic reversion mutations that improve export of maltose-binding protein in Escherichia coli malE signal sequence mutants.

Escherichia coli strains harboring malE signal sequence point mutations accumulate export-defective precursor maltose-binding protein (MBP) in the cytoplasm. Beginning with these mutants, a number of spontaneous intragenic revertants have been obtained in which export of the MBP to the periplasm is either partially or totally restored. With a single exception, each of the reversion mutations resulted in an increase in the overall hydrophobicity of the signal peptide hydrophobic core by one of five different mechanisms. In some revertants, MBP export was achieved at a rate comparable to the wild type MBP; in other cases, the rate of MBP export was significantly slower than wild type. The results indicate that the overall hydrophobicity of the signal peptide, rather than the absolute length of its uninterrupted hydrophobic core, is a major determinant of MBP export competency. An alteration at residue 19 of the mature MBP also has been identified that provides fairly efficient suppression of the export defect in the adjacent signal peptide, further suggesting that important export information may reside in this region of the precursor protein.

ATP-Binding Cassette Transporters↗
PubMed2005

Gene action of new mutations in Arabidopsis thaliana.

For a newly arising mutation affecting a trait under selection, its degree of dominance relative to the preexisting allele(s) strongly influences its evolutionary impact. We have estimated dominance parameters for spontaneous mutations in a subset of lines derived from a highly inbred founder of Arabidopsis thaliana by at least 17 generations of mutation accumulation (MA). The labor-intensive nature of the crosses and the anticipated subtlety of effects limited the number of MA lines included in this study to 8. Each MA line was selfed and reciprocally crossed to plants representing the founder genotype, and progeny were assayed in the greenhouse. Significant mutational effects on reproductive fitness included a recessive fitness-enhancing effect in one line and fitness-reducing effects, one additive and the other slightly recessive. Mutations conferring earlier phenology or smaller leaves were significantly recessive. For effects increasing leaf number and reducing height at flowering, additive gene action accounted for the expression of the traits. The sole example of a significantly dominant mutational effect delayed phenology. Our findings of recessive action of a fitness-enhancing mutational effect and additive action of a deleterious effect counter a common expectation of (partial) dominance of alleles that increase fitness, but the frequency of occurrence of such mutations is unknown.

Alleles↗
PubMed2001

A mitochondrial paradigm for degenerative diseases and ageing.

A variety of degenerative diseases have now been shown to be caused by mutations in mitochondrial genes encoded by the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). The mitochondria generate most of the cellular energy by oxidative phosphorylation (OXPHOS), and produce most of the toxic reactive oxygen species (ROS) as a by-product. Genetic defects that inhibit OXPHOS also cause the redirection of OXPHOS electrons into ROS production, thus increasing oxidative stress. A decline in mitochondrial energy production and an increase in oxidative stress can impinge on the mitochondrial permeability transition pore (mtPTP) to initiate programmed cell death (apoptosis). The interaction of these three factors appear to play a major role on the pathophysiology of degenerative diseases. Inherited diseases can result from mtDNA base substitution and rearrangement mutations and can affect the CNS, heart and skeletal muscle, and renal, endocrine and haematological systems. In addition, somatic mtDNA mutations accumulate with age in post-mitotic tissues in association with the age-related decline in mitochondrial function and are thought to be an important factor in ageing and senescence. The importance of mitochondrial defects in degenerative diseases and ageing has been demonstrated using mouse models of mitochondrial disease. An mtDNA mutation imparting chloramphenical resistance (CAPR) to mitochondrial protein synthesis has been transferred into mice and resulted in growth retardation and cardiomyopathy. A nDNA mutation which inactivates the heart-muscle isoform of the adenine nucleotide translocator (Ant1) results in mitochondrial myopathy and cardiomyopathy; induction of ROS production; the compensatory up-regulation of energy, antioxidant, and apoptosis gene expression; and an increase in the mtDNA somatic mutation rate. Finally, a nDNA mutation which inactivates the mitochondrial Mn superoxide dismutase (MnSOD) results in death in about 8 days due to dilated cardiomyopathy, which can be ameliorated by treatment with catalytic anti-oxidants. A partial MnSOD deficiency chronically increases oxidative stress, decreases OXPHOS function, and stimulates apoptosis. Thus, the decline of mitochondrial energy production resulting in increased oxidative stress and apoptosis does play a significant role in degenerative diseases and ageing.

Aging↗
PubMed1995

Impact of natural sequence variation in the V2 region of the envelope protein of human immunodeficiency virus type 1 on syncytium induction: a mutational analysis.

Several studies have demonstrated a functional role for the V1-V2 region of the human immunodeficiency virus type 1 (HIV-1) envelope surface glycoprotein gp120 in the membrane fusion processes underlying viral entry and syncytium induction. In a study with chimeric primary envelope genes, we have previously demonstrated that the exchange of V2 regions was sufficient to transfer syncytium-inducing capacity to a non-syncytium-inducing envelope protein. The exchanged V2 regions, comprising a number of variable amino acids, conferred changes to both the predicted secondary structure and to the net positive charge of the V2 loops. In a syncytium-forming assay based on transient envelope protein expression in CD4+ SupT1 cells, we have extended this observation by mutating the variable positions of the V2 region to determine the relative contribution of individual amino acids to syncytium formation. It can be shown that simultaneous mutation of multiple amino acids is needed to interfere with the V2 region-determined syncytium-inducing phenotype. Single amino acid changes either influencing charge of predicted secondary structure of the V2 loop proved to be insufficient to abolish V2 region-controlled syncytium formation. This robust V2 organization may allow the virus to accumulate mutations, while retaining its biological phenotype.

Amino Acid Sequence↗
PubMed2026

Caloric restriction modulates genome-wide somatic mutation in mice.

Somatic mutations accumulate throughout life in every cell, and this process constitutes one of the hallmarks of aging-genomic instability. Caloric restriction (CR) has been shown to extend lifespan across diverse species. Using high-fidelity duplex DNA sequencing of bulk liver, bulk kidney, hepatocytes, and cerebellar neurons, we found that CR in mice reduces genome-wide somatic mutation burdens across multiple tissues and cell types. CR reduced both substitution and insertion/deletion burdens, with the magnitude of these effects varying across sample types. CR also decreased the activity of the enigmatic single-base substitution (SBS) mutational process SBS5 that gives rise to most mutations in mammals. Surprisingly, the mutation burden reduction from CR was greatest in transcriptionally inactive regions. This work illuminates links between diet, aging, and genomic integrity and establishes genomic integrity as a modifiable axis of aging.

DNA↗