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Mutator Phenotype (mutator + phenotype)

Distribution by Scientific Domains

Medical Sciences	83%

Selected Abstracts

Effect of deletion of SOS-induced polymerases, pol II, IV, and V, on spontaneous mutagenesis in Escherichia coli mutD5

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 4 2004
Anetta Nowosielska
Abstract The E. coli dnaQ gene encodes the , subunit of DNA polymerase III (pol III) responsible for the proofreading activity of this polymerase. The mutD5 mutant of dnaQ chronically expresses the SOS response and exhibits a mutator phenotype. In this study we have constructed a set of E. coli AB1157 mutD5 derivatives deleted in genes encoding SOS-induced DNA polymerases, pol II, pol IV, and pol V, and estimated the frequency and specificity of spontaneous argE3,Arg+ reversion in exponentially growing and stationary-phase cells of these strains. We found that pol II exerts a profound effect on the specificity of spontaneous mutation in exponentially growing cells. Analysis of growth-dependent Arg+ revertants in mutD5 polB+ strains revealed that Arg+ revertants were due to tRNA suppressor formation, whereas those in mutD5 ,polB strains arose by back mutation at the argE3 ochre site. In stationary-phase bacteria, Arg+revertants arose mainly by back mutation, regardless of whether they were proficient or deficient in pol II. Our results also indicate that in a mutD5 background, the absence of pol II led to increased frequency of Arg+ growth-dependent revertants, whereas the lack of pol V caused its dramatic decrease, especially in mutD5 ,umuDC and mutD5 ,umuDC ,polB strains. In contrast, the rate of stationary-phase Arg+revertants increased in the absence of pol IV in the mutD5 ,dinB strain. We postulate that the proofreading activity of pol II excises DNA lesions in exponentially growing cells, whereas pol V and pol IV are more active in stationary-phase cultures. Environ. Mol. Mutagen. 43:226,234, 2004. © 2004 Wiley-Liss, Inc. [source]

Mutator phenotype confers advantage in Escherichia coli chronic urinary tract infection pathogenesis

FEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 3 2005
Francoise Labat
Abstract It has been suggested that mutator phenotype could be associated with an increase in virulence, but to date experimental evidences are lacking. Epidemiological studies have revealed that urinary tract infection isolates encompass the highest proportion of mutator strains within the Escherichia coli species. Using the uropathogenic strain CFT073 and its mutS+ mutator mutant, we show that the mutator strain is selected in vitro in urine and in the late stages of infection in a mouse model having urinary tract infection. Thus, we report that, under specific conditions, i.e., urinary tract infection, the mutator phenotype may confer an advantage in pathogenesis. [source]

Aberrant expression of cell-cycle regulator cyclin D1 in breast cancer is related to chromosomal genomic instability

GENES, CHROMOSOMES AND CANCER, Issue 3 2002
Jia-Chyi Lung
To account for the accumulation of genomic alterations required for tumor progression, it has been suggested that the genomes of cancer cells are unstable and that this instability results from defective mutators (the "mutator phenotype" theory). To examine the hypothesis that abnormal cell-cycle regulators act as the mutators contributing to genomic instability, the present study, based on primary tumor tissues from 71 patients with breast cancer, was performed to determine whether there was an association between aberrant expression of cell-cycle regulators (cyclin A, cyclin D1, cyclin E, RB1, p21, and p27) and chromosomal instability. Comparative genomic hybridization was used to measure chromosomal changes, reflecting genomic instability in individual tumors, whereas immunohistochemistry was used to detect aberrant expression of cell-cycle regulators. Overexpression of cyclin D1 was found to be significantly correlated with increased chromosomal instability (defined as harboring more than 7 chromosomal changes), with 63% of tumors overexpressing and 27% of tumors not overexpressing, with cyclin D1 showing chromosomal instability (P < 0.05). Interestingly, this relationship was independent of cell outgrowth (as detected by the proliferation marker Ki-67) and was particularly significant in tumors not expressing p27 or in tumors with detectable RB1. These results suggest that cyclin D1 plays an alternative role in the regulation of genomic stability. © 2002 Wiley-Liss, Inc. [source]

Evolution and spread of antibiotic resistance

JOURNAL OF INTERNAL MEDICINE, Issue 2 2002
B. Henriques Normark
Abstract., Antibiotic resistance is a clinical and socioeconomical problem that is here to stay. Resistance can be natural or acquired. Some bacterial species, such as Pseudomonas aeruginosa, show a high intrinsic resistance to a number of antibiotics whereas others are normally highly antibiotic susceptible such as group A streptococci. Acquired resistance evolve via genetic alterations in the microbes own genome or by horizontal transfer of resistance genes located on various types of mobile DNA elements. Mutation frequencies to resistance can vary dramatically depending on the mechanism of resistance and whether or not the organism exhibits a mutator phenotype. Resistance usually has a biological cost for the microorganism, but compensatory mutations accumulate rapidly that abolish this fitness cost, explaining why many types of resistances may never disappear in a bacterial population. Resistance frequently occurs stepwise making it important to identify organisms with low level resistance that otherwise may constitute the genetic platform for development of higher resistance levels. Self-replicating plasmids, prophages, transposons, integrons and resistance islands all represent DNA elements that frequently carry resistance genes into sensitive organisms. These elements add DNA to the microbe and utilize site-specific recombinases/integrases for their integration into the genome. However, resistance may also be created by homologous recombination events creating mosaic genes where each piece of the gene may come from a different microbe. The selection with antibiotics have informed us much about the various genetic mechanisms that are responsible for microbial evolution. [source]

Microsatellite instability of papillary subtype of human gastric adenocarcinoma and hMLH1 promoter hypermethylation in the surrounding mucosa

PATHOLOGY INTERNATIONAL, Issue 4 2001
Rong-Jun Guo
Gastric cancer has striking heterogeneity in histological pattern, cellular phenotype, genotype, biomarkers, and biological behavior. We focused on the specific morphological papillary phenotype of gastric adenocarcinoma and attempted to identify its distinct molecular characteristics. In our comparative study, early stage papillary (papillary-dominant) gastric cancer showed a significantly higher and more widespread high-frequency microsatellite instability (MSI-H) than other morphological types. Analysis of mutations in a panel of five putative microsatellite instability (MSI)-associated genes in the MSI-H cases revealed that papillary or papillary-dominant cancer displays a unique profile of mutations compared to profiles previously reported in gastric cancer. Immunohistochemical staining and methylation analysis revealed that silencing of hMLH1 by methylation in its promoter region was responsible for the failure of mismatch repair in papillary-type gastric cancer, whereas aberrant promoter methylation of hMLH1 was not found in any cases without the unique mutator phenotype. Promoter hypermethylation of the hMLH1 genes was found to a lesser degree in the adjacent non-tumor mucosa in four of the 10 cases with tumor having the mutator phenotype. Microsatellite instability itself could not be detected in the adjacent non-tumor mucosa. Inactivation of hMLH1 expression by promoter hypermethylation may be an early event in carcinogenesis of this type of gastric cancer, preceding the development of the clear MSI phenotype of papillary carcinoma. [source]