The Experts below are selected from a list of 252 Experts worldwide ranked by ideXlab platform
Susan M. Rosenberg - One of the best experts on this subject based on the ideXlab platform.
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Oxygen and RNA in stress-Induced Mutation.
Current Genetics, 2018Co-Authors: Raul Correa, P. C. Thornton, Susan M. Rosenberg, P. J. HastingsAbstract:Mechanisms of Mutation upregulated by stress responses have been described in several organisms from bacteria to human. These mechanisms might accelerate genetic change specifically when cells are maladapted to their environment. Stress-Induced Mutation mechanisms differ in their genetic requirements from Mutation in growing cells, occurring by different mechanisms in different assay systems, but having in common a requirement for the induction of stress-responses. Here, we review progress in two areas relevant to stress-response-dependent mutagenic DNA break repair mechanisms in Escherichia coli. First, we review evidence that relates Mutation to transcription. This connection might allow mutagenesis in transcribed regions, including those relevant to any stress being experienced, opening the possibility that Mutations could be targeted to regions where Mutation might be advantageous under conditions of a specific stress. We review the mechanisms by which replication initiated by transcription can lead to Mutation. Second, we review recent findings that, although stress-Induced Mutation does not require exogenous DNA-damaging agents, it does require the presence of damaged bases in DNA. For starved E. coli, endogenous oxygen radicals cause these altered bases. We postulate that damaged bases stall the replisome, which, we suggest, is required for DNA-polymerase exchange, allowing the action of low-fidelity DNA polymerases that promote Mutation.
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stress Induced Mutation via dna breaks in escherichia coli a molecular mechanism with implications for evolution and medicine
BioEssays, 2012Co-Authors: Susan M. Rosenberg, Chandan Shee, Ryan L Frisch, P. J. HastingsAbstract:Evolutionary theory assumed that Mutations occur constantly, gradually, and randomly over time. This formulation from the “modern synthesis” of the 1930s was embraced decades before molecular understanding of genes or Mutations. Since then, our labs and others have elucidated Mutation mechanisms activated by stress responses. Stress-Induced Mutation mechanisms produce Mutations, potentially accelerating evolution, specifically when cells are maladapted to their environment, that is, when they are stressed. The mechanisms of stress-Induced Mutation that are being revealed experimentally in laboratory settings provide compelling models for mutagenesis that propels pathogen–host adaptation, antibiotic resistance, cancer progression and resistance, and perhaps much of evolution generally. We discuss double-strand-break-dependent stress-Induced Mutation in Escherichia coli. Recent results illustrate how a stress response activates mutagenesis and demonstrate this mechanism's generality and importance to spontaneous Mutation. New data also suggest a possible harmony between previous, apparently opposed, models for the molecular mechanism. They additionally strengthen the case for anti-evolvability therapeutics for infectious disease and cancer.
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What limits the efficiency of double-strand break-dependent stress-Induced Mutation in Escherichia coli?
Journal of Molecular Microbiology and Biotechnology, 2012Co-Authors: Chandan Shee, Rebecca G. Ponder, Janet L. Gibson, Susan M. RosenbergAbstract:Stress-Induced Mutation is a collection of molecular mechanisms in bacterial, yeast and human cells that promote mutagenesis specifically when cells are maladapted to their environment, i.e. when they
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a switch from high fidelity to error prone dna double strand break repair underlies stress Induced Mutation
Molecular Cell, 2005Co-Authors: Rebecca G. Ponder, Natalie C Fonville, Susan M. RosenbergAbstract:Special mechanisms of Mutation are Induced in microbes under growth-limiting stress causing genetic instability, including occasional adaptive Mutations that may speed evolution. Both the Mutation mechanisms and their control by stress have remained elusive. We provide evidence that the molecular basis for stress-Induced mutagenesis in an E. coli model is error-prone DNA double-strand break repair (DSBR). I-SceI-endonuclease-Induced DSBs strongly activate stress-Induced Mutations near the DSB, but not globally. The same proteins are required as for cells without Induced DSBs: DSBR proteins, DinB-error-prone polymerase, and the RpoS starvation-stress-response regulator. Mutation is promoted by homology between cut and uncut DNA molecules, supporting a homology-mediated DSBR mechanism. DSBs also promote gene amplification. Finally, DSBs activate Mutation only during stationary phase/starvation but will during exponential growth if RpoS is expressed. Our findings reveal an RpoS-controlled switch from high-fidelity to mutagenic DSBR under stress. This limits genetic instability both in time and to localized genome regions, potentially important evolutionary strategies.
Hanshenrik M Dahl - One of the best experts on this subject based on the ideXlab platform.
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an enu Induced Mutation of cdh23 causes congenital hearing loss but no vestibular dysfunction in mice
American Journal of Pathology, 2011Co-Authors: Shehnaaz S M Manji, Kerry A Miller, Louise H Williams, Lotte Andreasen, Maria Siboe, Elizabeth Rose, Melanie Bahlo, Michael J Kuiper, Hanshenrik M DahlAbstract:Mutations in the human cadherin 23 (CDH23) gene cause deafness, neurosensory, autosomal recessive 12 (DFNB12) nonsyndromic hearing loss or Usher syndrome, type 1D (characterized by hearing impairment, vestibular dysfunction, and visual impairment). Reported waltzer mouse strains each harbor a Cdh23-null Mutation and present with hearing loss and vestibular dysfunction. Two additional Cdh23 mouse mutants, salsa and erlong, each carry a homozygous Cdh23 missense Mutation and have progressive hearing loss. We report the identification of a novel mouse strain, jera, with inherited hearing loss caused by an N-ethyl-N-nitrosourea–Induced c.7079T>A Mutation in the Cdh23 gene. The Mutation generates a missense change, p.V2360E, in Cdh23. Affected mice have profound sensorineural deafness, with no vestibular dysfunction. The p.V2360E Mutation is semidominant because heterozygous mice have milder and more progressive hearing loss in advanced age. The Mutation affects a highly conserved Ca2+-binding motif in extracellular domain 22, thought to be important for Cdh23 structure and dimerization. Molecular modeling suggests that the Cdh23V2360E/V2360E Mutation alters the structural conformation of the protein and affects Ca2+-binding properties. Similar to salsa mice, but in contrast to waltzer mice, hair bundle development is normal in jera and hearing loss appears to be due to the loss of tip links. Thus, jera is a novel mouse model for DFNB12.
P. J. Hastings - One of the best experts on this subject based on the ideXlab platform.
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Oxygen and RNA in stress-Induced Mutation.
Current Genetics, 2018Co-Authors: Raul Correa, P. C. Thornton, Susan M. Rosenberg, P. J. HastingsAbstract:Mechanisms of Mutation upregulated by stress responses have been described in several organisms from bacteria to human. These mechanisms might accelerate genetic change specifically when cells are maladapted to their environment. Stress-Induced Mutation mechanisms differ in their genetic requirements from Mutation in growing cells, occurring by different mechanisms in different assay systems, but having in common a requirement for the induction of stress-responses. Here, we review progress in two areas relevant to stress-response-dependent mutagenic DNA break repair mechanisms in Escherichia coli. First, we review evidence that relates Mutation to transcription. This connection might allow mutagenesis in transcribed regions, including those relevant to any stress being experienced, opening the possibility that Mutations could be targeted to regions where Mutation might be advantageous under conditions of a specific stress. We review the mechanisms by which replication initiated by transcription can lead to Mutation. Second, we review recent findings that, although stress-Induced Mutation does not require exogenous DNA-damaging agents, it does require the presence of damaged bases in DNA. For starved E. coli, endogenous oxygen radicals cause these altered bases. We postulate that damaged bases stall the replisome, which, we suggest, is required for DNA-polymerase exchange, allowing the action of low-fidelity DNA polymerases that promote Mutation.
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stress Induced Mutation via dna breaks in escherichia coli a molecular mechanism with implications for evolution and medicine
BioEssays, 2012Co-Authors: Susan M. Rosenberg, Chandan Shee, Ryan L Frisch, P. J. HastingsAbstract:Evolutionary theory assumed that Mutations occur constantly, gradually, and randomly over time. This formulation from the “modern synthesis” of the 1930s was embraced decades before molecular understanding of genes or Mutations. Since then, our labs and others have elucidated Mutation mechanisms activated by stress responses. Stress-Induced Mutation mechanisms produce Mutations, potentially accelerating evolution, specifically when cells are maladapted to their environment, that is, when they are stressed. The mechanisms of stress-Induced Mutation that are being revealed experimentally in laboratory settings provide compelling models for mutagenesis that propels pathogen–host adaptation, antibiotic resistance, cancer progression and resistance, and perhaps much of evolution generally. We discuss double-strand-break-dependent stress-Induced Mutation in Escherichia coli. Recent results illustrate how a stress response activates mutagenesis and demonstrate this mechanism's generality and importance to spontaneous Mutation. New data also suggest a possible harmony between previous, apparently opposed, models for the molecular mechanism. They additionally strengthen the case for anti-evolvability therapeutics for infectious disease and cancer.
Toshiyuki Norimura - One of the best experts on this subject based on the ideXlab platform.
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comparison of the frequency of t cell receptor mutants and thioguanine resistance Induced by x rays and ethylnitrosourea in cultured human blood t lymphocytes
Mutation Research, 1996Co-Authors: Naoki Kunugita, Satoshi Nomoto, Toshiyuki NorimuraAbstract:Abstract We have investigated two assays for measuring the induction of Mutations using human T-lymphocytes isolated from leukocyte residue buffy coats obtained from normal donors. Variant cell frequency of T-cells defective in the T-cell receptor (TCR) gene expression was measured using a 2-color flow cytometry, and 6-thioguanine-resistant (TG r ) cells were determined using a cloning technique at the HPRT gene after treatment with 250 kVp X-rays or ethylnitrosourea (ENU). The frequencies of TCR mutant cells as well as those of TG r cells increased with increasing doses of X-rays or concentrations of ENU studied. For TCR mutants, the Induced Mutation frequencies at D 37 (giving 37% survival) were 31.7 × 10 −4 and 11.0 × 10 −4 for X-rays and ENU, respectively. For TG r T-cells, the Induced Mutation frequencies at D 37 for the same mutagens were 14.4 × 10 −6 and 75.5 × 10 −6 , respectively. Over the dose range studied, the relationship appears to be linear between the Mutation induction of TCR and that of TG r for X-rays or ENU. However, X-rays may induce more TCR mutants against less induction TG r T-cells, and ENU may cause a reverse result. The sensitivity of the assay of each biological endpoint in human blood T-lymphocytes may be different.
Martin Brendel - One of the best experts on this subject based on the ideXlab platform.
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RNR4 mutant alleles pso3-1 and rnr4Δ block Induced Mutation in Saccharomyces cerevisiae
Current Genetics, 2007Co-Authors: Martin Strauss, Martin Grey, João Antonio Pegas Henriques, Martin BrendelAbstract:The PSO3 gene of Saccharomyces cerevisiae was molecularly cloned by complementing the cold-sensitivity phenotype of a pso3-1 mutant and was found to be allelic to RNR4 , encoding one of the two DNA damage-inducible small subunits of the ribonucleotide reductase (RNR) complex. Compared to a rnr4 Δ mutant that allows only very little Mutation induction at very low doses of 254_nm ultraviolet light (UVC), the pso3-1 mutant allele confers leakiness in that it permits some DNA damage-Induced mutagenesis at low doses of UVC. Similarly, the pso3 mutant is slightly less sensitive to UVC than an rnr4 Δ mutant. Cloning and sequencing of the RNR4 locus of the pso3-1 mutant revealed that its intermediate phenotype is attributable to a G → A transition at nucleotide 352, leading to replacement of glycine by arginine [G118R] in the mutant’s protein. Both RNR4 mutant alleles confer significantly less sensitivity to UVC than mutant alleles of non-UVC-mutable REV3 , indicating that, apart from nucleotide excision repair, RAD6 -dependent error-free DNA repair may still be functional. The phenotype of a strongly reduced UVC-Induced mutagenesis for rnr4 mutant alleles has not yet been described; it suggests the importance of this gene for a fully functional RNR providing correct amounts of DNA precursor molecules, thereby, allowing translesion synthesis (error-prone) of UVC-damaged DNA. Stationary phase cells of the rnr4 Δ mutant, but not of the original pso3-1 mutant, are swollen with a fourfold to eightfold increase in volume. The central role of RNR in DNA precursor metabolism and its complex regulation allow for several modes of suppression that may influence the phenotypes of RNR4 mutants, especially those containing the leaky pso3-1 mutant allele.