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Sue Jinksrobertson - One of the best experts on this subject based on the ideXlab platform.
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Mitotic Recombination in yeast what we know and what we don t know
Current Opinion in Genetics & Development, 2021Co-Authors: Sue Jinksrobertson, Thomas D PetesAbstract:Saccharomyces cerevisiae is at the forefront of defining the major Recombination mechanisms/models that repair targeted double-strand breaks during mitosis. Each of these models predicts specific molecular intermediates as well as genetic outcomes. Recent use of single-nucleotide polymorphisms to track the exchange of sequences in Recombination products has provided an unprecedented level of detail about the corresponding intermediates and the extents to which different mechanisms are utilized. This approach also has revealed complexities that are not predicted by canonical models, suggesting that modifications to these models are needed. Current data are consistent with the initiation of most inter-homolog spontaneous Mitotic Recombination events by a double-strand break. In addition, the sister chromatid is preferred over the homolog as a repair template.
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mismatch recognition and subsequent processing have distinct effects on Mitotic Recombination intermediates and outcomes in yeast
Nucleic Acids Research, 2019Co-Authors: Sue JinksrobertsonAbstract:: The post-replicative mismatch repair (MMR) system has anti-Recombination activity that limits interactions between diverged sequences by recognizing mismatches in strand-exchange intermediates. In contrast to their equivalent roles during replication-error repair, mismatch recognition is more important for anti-Recombination than subsequent mismatch processing. To obtain insight into this difference, ectopic substrates with 2% sequence divergence were used to examine Mitotic Recombination outcome (crossover or noncrossover; CO and NCO, respectively) and to infer molecular intermediates formed during double-strand break repair in Saccharomyces cerevisiae. Experiments were performed in an MMR-proficient strain, a strain with compromised mismatch-recognition activity (msh6Δ) and a strain that retained mismatch-recognition activity but was unable to process mismatches (mlh1Δ). While the loss of either mismatch binding or processing elevated the NCO frequency to a similar extent, CO events increased only when mismatch binding was compromised. The molecular features of NCOs, however, were altered in fundamentally different ways depending on whether mismatch binding or processing was eliminated. These data suggest a model in which mismatch recognition reverses strand-exchange intermediates prior to the initiation of end extension, while subsequent mismatch processing that is linked to end extension specifically destroys NCO intermediates that contain conflicting strand-discrimination signals for mismatch removal.
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effects of mismatch repair and hpr1 on transcription stimulated Mitotic Recombination in the yeast saccharomyces cerevisiae
DNA Repair, 2004Co-Authors: Jennifer A Freedman, Sue JinksrobertsonAbstract:High levels of transcription driven by the GAL1-10 promoter stimulate Mitotic Recombination between direct repeats (DR) as well as between substrates positioned on non-homologous chromosomes. When the substrates are on non-homologous chromosomes, transcription stimulates both gene conversion and crossover events, but the degree of the stimulation varies depending on which substrate is highly transcribed. In gene conversion assays where only one of the substrates is highly transcribed, the effect of transcribing the donor versus the recipient allele can be highly asymmetric. We have examined the basis of this asymmetry and demonstrate that it relates to the nature of the mismatch present in Recombination intermediates and the presence of the Msh3 mismatch repair (MMR) protein. In addition to examining the asymmetry conferred by donor versus recipient allele transcription, the possible contribution of transcription elongation problems to transcription-stimulated Recombination has been examined using hpr1 mutants. Hpr1 is important for efficient elongation through certain sequences, and in hpr1 mutants, elongation problems have been correlated with elevated Recombination between direct repeats. As expected, we found that combining loss of Hpr1 with high levels of transcription had very strong synergistic effects on Recombination rates between direct repeats. When the substrates were on non-homologous chromosomes, a weaker synergistic interaction between transcription and Hpr1 loss was observed in gene conversion assays, but only an additive relationship was observed in a crossover-specific assay. Although these data support a causal link between transcription elongation problems and elevated Recombination rates, they also indicate that high levels of transcription can stimulate Recombination by additional mechanisms. © 2004 Elsevier B.V. All rights reserved.
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genetic requirements for spontaneous and transcription stimulated Mitotic Recombination in saccharomyces cerevisiae
Genetics, 2002Co-Authors: Jennifer A Freedman, Sue JinksrobertsonAbstract:The genetic requirements for spontaneous and transcription-stimulated Mitotic Recombination were determined using a Recombination system that employs heterochromosomal lys2 substrates that can recombine only by crossover or only by gene conversion. The substrates were fused either to a constitutive low-level promoter ( pLYS ) or to a highly inducible promoter ( pGAL ). In the case of the “conversion-only” substrates the use of heterologous promoters allowed either the donor or the recipient allele to be highly transcribed. Transcription of the donor allele stimulated gene conversions in rad50, rad51, rad54 , and rad59 mutants, but not in rad52, rad55 , and rad57 mutants. In contrast, transcription of the recipient allele stimulated gene conversions in rad50, rad51, rad54, rad55, rad57 , and rad59 mutants, but not in rad52 mutants. Finally, transcription stimulated crossovers in rad50, rad54 , and rad59 mutants, but not in rad51, rad52, rad55 , and rad57 mutants. These data are considered in relation to previously proposed molecular mechanisms of transcription-stimulated Recombination and in relation to the roles of the Recombination proteins.
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stimulation of Mitotic Recombination events by high levels of rna polymerase ii transcription in yeast
Molecular and Cellular Biology, 2000Co-Authors: Dean Saxe, Abhijit Datta, Sue JinksrobertsonAbstract:The impact of high levels of RNA polymerase II transcription on Mitotic Recombination was examined using lys2 Recombination substrates positioned on nonhomologous chromosomes. Substrates were used that could produce Lys(+) recombinants by either a simple (noncrossover) gene conversion event or a crossover-associated Recombination event, by only a simple gene conversion event, or by only a crossover event. Transcription of the lys2 substrates was regulated by the highly inducible GAL1-10 promoter or the low-level LYS2 promoter, with GAL1-10 promoter activity being controlled by the presence or absence of the Gal80p negative regulatory protein. Transcription was found to stimulate Recombination in all assays used, but the level of stimulation varied depending on whether only one or both substrates were highly transcribed. In addition, there was an asymmetry in the types of Recombination events observed when one substrate versus the other was highly transcribed. Finally, the lys2 substrates were positioned as direct repeats on the same chromosome and were found to exhibit a different Recombinational response to high levels of transcription from that exhibited by the repeats on nonhomologous chromosomes. The relevance of these results to the mechanisms of transcription-associated Recombination are discussed.
Thomas D Petes - One of the best experts on this subject based on the ideXlab platform.
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Mitotic Recombination in yeast what we know and what we don t know
Current Opinion in Genetics & Development, 2021Co-Authors: Sue Jinksrobertson, Thomas D PetesAbstract:Saccharomyces cerevisiae is at the forefront of defining the major Recombination mechanisms/models that repair targeted double-strand breaks during mitosis. Each of these models predicts specific molecular intermediates as well as genetic outcomes. Recent use of single-nucleotide polymorphisms to track the exchange of sequences in Recombination products has provided an unprecedented level of detail about the corresponding intermediates and the extents to which different mechanisms are utilized. This approach also has revealed complexities that are not predicted by canonical models, suggesting that modifications to these models are needed. Current data are consistent with the initiation of most inter-homolog spontaneous Mitotic Recombination events by a double-strand break. In addition, the sister chromatid is preferred over the homolog as a repair template.
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high resolution mapping of heteroduplex dna formed during uv induced and spontaneous Mitotic Recombination events in yeast
eLife, 2017Co-Authors: Yi Yin, Margaret Dominska, Eunice Yim, Thomas D PetesAbstract:In yeast, DNA breaks are usually repaired by homologous Recombination (HR). An early step for HR pathways is formation of a heteroduplex, in which a single-strand from the broken DNA molecule pairs with a strand derived from an intact DNA molecule. If the two strands of DNA are not identical, there will be mismatches within the heteroduplex DNA (hetDNA). In wild-type strains, these mismatches are repaired by the mismatch repair (MMR) system, producing a gene conversion event. In strains lacking MMR, the mismatches persist. Most previous studies involving hetDNA formed during Mitotic Recombination were restricted to one locus. Below, we present a global mapping of hetDNA formed in the MMR-defective mlh1 strain. We find that many Recombination events are associated with repair of double-stranded DNA gaps and/or involve Mlh1-independent mismatch repair. Many of our events are not explicable by the simplest form of the double-strand break repair model of Recombination.
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genome wide high resolution mapping of uv induced Mitotic Recombination events in saccharomyces cerevisiae
PLOS Genetics, 2013Co-Authors: Yi Yin, Thomas D PetesAbstract:In the yeast Saccharomyces cerevisiae and most other eukaryotes, Mitotic Recombination is important for the repair of double-stranded DNA breaks (DSBs). Mitotic Recombination between homologous chromosomes can result in loss of heterozygosity (LOH). In this study, LOH events induced by ultraviolet (UV) light are mapped throughout the genome to a resolution of about 1 kb using single-nucleotide polymorphism (SNP) microarrays. UV doses that have little effect on the viability of diploid cells stimulate crossovers more than 1000-fold in wild-type cells. In addition, UV stimulates Recombination in G1-synchronized cells about 10-fold more efficiently than in G2-synchronized cells. Importantly, at high doses of UV, most conversion events reflect the repair of two sister chromatids that are broken at approximately the same position whereas at low doses, most conversion events reflect the repair of a single broken chromatid. Genome-wide mapping of about 380 unselected crossovers, break-induced replication (BIR) events, and gene conversions shows that UV-induced Recombination events occur throughout the genome without pronounced hotspots, although the ribosomal RNA gene cluster has a significantly lower frequency of crossovers.
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high resolution mapping of spontaneous Mitotic Recombination hotspots on the 1 1 mb arm of yeast chromosome iv
PLOS Genetics, 2013Co-Authors: Jordan St Charles, Thomas D PetesAbstract:Although homologous Recombination is an important pathway for the repair of double-stranded DNA breaks in Mitotically dividing eukaryotic cells, these events can also have negative consequences, such as loss of heterozygosity (LOH) of deleterious mutations. We mapped about 140 spontaneous reciprocal crossovers on the right arm of the yeast chromosome IV using single-nucleotide-polymorphism (SNP) microarrays. Our mapping and subsequent experiments demonstrate that inverted repeats of Ty retrotransposable elements are Mitotic Recombination hotspots. We found that the Mitotic Recombination maps on the two homologs were substantially different and were unrelated to meiotic Recombination maps. Additionally, about 70% of the DNA lesions that result in LOH are likely generated during G1 of the cell cycle and repaired during S or G2. We also show that different genetic elements are associated with reciprocal crossover conversion tracts depending on the cell cycle timing of the initiating DSB.
Jay A Tischfield - One of the best experts on this subject based on the ideXlab platform.
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ionizing radiation is a potent inducer of Mitotic Recombination in mouse embryonic stem cells
Mutation Research, 2011Co-Authors: Natalia G Denissova, Changshun Shao, Peter J Stambrook, Irina V Tereshchenko, Eric Cui, Jay A TischfieldAbstract:Maintenance of genomic integrity in embryonic cells is pivotal to proper embryogenesis, organogenesis and to the continuity of species. Cultured mouse embryonic stem cells (mESCs), a model for early embryonic cells, differ from cultured somatic cells in their capacity to remodel chromatin, in their repertoire of DNA repair enzymes, and in the regulation of cell cycle checkpoints. Using 129XC3HF1 mESCs heterozygous for Aprt, we characterized loss of Aprt heterozygosity after exposure to ionizing radiation. We report here that the frequency of loss of heterozygosity mutants in mESCs can be induced several hundred-fold by exposure to 5-10Gy of X-rays. This induction is 50-100-fold higher than the induction reported for mouse adult or embryonic fibroblasts. The primary mechanism underlying the elevated loss of heterozygosity after irradiation is Mitotic Recombination, with lesser contributions from deletions and gene conversions that span Aprt. Aprt point mutations and epigenetic inactivation are very rare in mESCs compared to fibroblasts. Mouse ESCs, therefore, are distinctive in their response to ionizing radiation and studies of differentiated cells may underestimate the mutagenic effects of ionizing radiation on ESC or other stem cells. Our findings are important to understanding the biological effects of ionizing radiation on early development and carcinogenesis.
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Mlh1 mediates tissue-specific regulation of Mitotic Recombination
Oncogene, 2004Co-Authors: Changshun Shao, Peter J Stambrook, Li Deng, Yanping Chen, Raju Kucherlapati, Jay A TischfieldAbstract:Mitotic Recombination (MR) between chromosome homologs in somatic cells is a major pathway to the loss of heterozygosity (LOH), which may cause cancer if tumor suppressor genes are involved. MR can be suppressed by DNA sequence heterology (homeology) in hybrid mice from matings between species or between subspecies. We now report that MR is relatively suppressed in F1 hybrids between inbred strains C57BL/6 and 129S2. The frequency of MR in fibroblasts is lower in F1 hybrid mice than in either of the two parental strains. However, MR in T cells is not affected by strain background. Thus, relatively small genetic differences are capable of restricting MR in a tissue-specific manner. Using Mlh1 -deficient mice, we tested the role of mismatch repair in MR in two isogenic cell types. In fibroblasts of C57BL/6 × 129S2 F1 mice, the suppression of MR is alleviated in the absence of MLH1. In contrast, MR is not affected by Mlh1 status in T cells. The frequency of point mutations at the reporter gene loci Aprt and Hprt , on the other hand, is significantly increased in both T cells and fibroblasts of Mlh1 ^−/− mice. Thus, different cell types respond differently to MLH1 deficiency, and the contribution of MR to tumorigenesis may be tissue-dependent in the absence of mismatch repair.
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Mitotic Recombination is suppressed by chromosomal divergence in hybrids of distantly related mouse strains
Nature Genetics, 2001Co-Authors: Changshun Shao, Peter J Stambrook, Jay A TischfieldAbstract:Mitotic Recombination occurs with high frequency in humans1,2 and mice3. It leads to loss of heterozygosity (LOH) at important gene loci and can cause disease4,5,6,7. However, the genetic modulators of Mitotic Recombination are not well understood. As Recombination depends on a high level of nucleotide sequence homology8,9,10,11,12, we postulate that the frequency of somatic variants derived from Mitotic Recombination should be diminished in progeny from crosses between strains of mice in which nucleotide sequences have diverged. Here we report that Mitotic Recombination is suppressed, to various degrees in different tissues, in hybrids of distantly related mouse strains. Reintroduction of greater chromosomal homology by backcrossing restores Mitotic Recombination in offspring. Thus, chromosomal divergence inhibits Mitotic Recombination and, consequently, may act as a modifier of cancer susceptibility by limiting the rate of LOH. The suppression of Mitotic Recombination in some F1 hybrids in which meiotic Recombination persists indicates that these processes are differentially affected by chromosomal divergence.
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Mitotic Recombination produces the majority of recessive fibroblast variants in heterozygous mice
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Changshun Shao, Peter J Stambrook, Li Deng, Octavian Henegariu, Li Liang, Nandita S Raikwar, Amrik Sahota, Jay A TischfieldAbstract:Mice heterozygous at Aprt (adenine phosphoribosyltransferase) were used as a model to study in vivo loss of heterozygosity (LOH) in normal fibroblasts. Somatic cell variants that exhibited functional loss of the wild-type Aprt in vivo were recovered as APRT-deficient cell colonies after culturing in selection medium containing 2,6-diaminopurine (DAP), an adenine analog that is toxic only to cells with APRT enzyme activity. DAP-resistant (DAPr) fibroblast variants were recovered at a median frequency of 12 × 10−5 from individual ears from progeny of crosses between mouse strains 129/Sv and C3H/HeJ. The frequency of DAPr variants varied greatly among individual ears, suggesting that they preexisted in vivo and arose at various times during development. Polymorphic molecular markers and a cytological marker on the centromere of chromosome 8 made it possible to discriminate between each of six possible mechanistic pathways of LOH. The majority (about 80%) of the DAPr variants were a consequence of Mitotic Recombination. The prevalence of Mitotic Recombination in regions proximal to Aprt did not correlate with meiotic map distances. In particular, there was a higher than expected frequency of crossovers within the interval 59 cM to 67 cM. The high spontaneous frequency of Aprt LOH, mediated primarily by Mitotic Recombination, is fully consistent with our previous results with human peripheral T cells from individuals known to be heterozygous at APRT. Thus, this Aprt heterozygote mouse is a valid model for studying somatic mutagenesis and Mitotic Recombination in vivo.
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high frequency in vivo loss of heterozygosity is primarily a consequence of Mitotic Recombination
Cancer Research, 1997Co-Authors: P K Gupta, Changshun Shao, Peter J Stambrook, Amrik Sahota, Simeon A Boyadjiev, S Bye, J P Oneill, T C Hunter, Richard J Albertini, Jay A TischfieldAbstract:We have used the adenine phosphoribosyltransferase gene (APRT; 16q24) to investigate the mechanisms of loss of heterozygosity (LOH) in normal human somatic cells in vivo. APRT-deficient (APRT-/-, APRT-/0) T lymphocytes from the peripheral blood of four obligate APRT heterozygotes (APRT+/-) with characterized germ-line mutations were selected in medium containing 100 microM 2,6-diaminopurine. A total of 80 2,6-diaminopurine-resistant T-cell clones from 2 of the heterozygotes were analyzed for this study. The presence or absence of LOH of proximal linked microsatellite repeat markers was used to divide the clones into two groups: (a) those in which LOH was likely due to localized changes in APRT (e.g., point mutations); and (b) those with LOH at additional loci. A total of 61 clones (76%) exhibited LOH of linked microsatellite repeat markers at different locations on 16q, which extended from the smallest measured region (<5.5 cM) to the entire 16q arm. The remaining 19 clones (24%) had point mutations in APRT or other relatively minor alterations. Ten clones with LOH encompassing different regions of 16q were examined by conventional cytogenetics and by fluorescence in situ hybridization using an APRT cosmid probe. All clones exhibited a normal diploid karyotype, and nine exhibited two copies of APRT. The one clone that was hemizygous for APRT had the smallest observed region of LOH in clones from that individual. These results indicate that Mitotic Recombination and, to a much lesser extent, deletion may be the primary mechanisms for the relatively high frequency of in vivo LOH observed in normal human T cells. Because LOH leads to the expression of recessive tumor suppressor genes in many cancers, these data have significant implications for the role of LOH in the early stages of tumor development, especially in breast cancer.
Andres Aguilera - One of the best experts on this subject based on the ideXlab platform.
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Mitotic Recombination in saccharomyces cerevisiae
Current Genetics, 2003Co-Authors: Felix Prado, Felipe Cortesledesma, Pablo Huertas, Andres AguileraAbstract:Mitotic homologous Recombination (HR) is an important mechanism for the repair of double-strand breaks and errors occurring during DNA replication. It is likely that the Recombinational repair of DNA lesions occurs preferentially by sister chromatid exchanges that have no genetic consequences. However, most genetically detectable HR events occur between homologous DNA sequences located at allelic positions in homologous chromosomes, or between DNA repeats located at ectopic positions in either the same, homologous or heterologous chromosomes. Mitotic Recombination may occur by multiple mechanisms, including double-strand break repair, synthesis-dependent strand annealing, break-induced replication and single-strand annealing. The occurrence of one Recombination mechanism versus another depends on different elements, including the position of the homologous partner, the initiation event, the length of homology of the recombinant molecules and the genotype. The genetics and molecular biology of the yeast Saccharomyces cerevisiae have proved essential for the understanding of Mitotic Recombination mechanisms in eukaryotes. Here, we review recent genetic yeast data that contribute to our understanding of the different mechanisms of Mitotic Recombination and the in vivo role of the Recombination proteins.
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a new hyperRecombination mutation identifies a novel yeast gene thp1 connecting transcription elongation with Mitotic Recombination
Genetics, 2001Co-Authors: Mercedes Gallardo, Andres AguileraAbstract:Given the importance of the incidence of Recombination in genomic instability, it is of great interest to know the elements or processes controlling Recombination in mitosis. One such process is transcription, which has been shown to induce Recombination in bacteria, yeast, and mammals. To further investigate the genetic control of the incidence of Recombination and genetic instability and, in particular, its connection with transcription, we have undertaken a search for hyperRecombination mutants among a large number of strains deleted in genes of unknown function. We have identified a new gene, THP1 (YOL072w), whose deletion mutation strongly stimulates Recombination between repeats. In addition, thp1 Delta impairs transcription, a defect that is particularly strong at the level of elongation through particular DNA sequences such as lacZ. The hyperRecombination phenotype of thp1 Delta cells is fully dependent on transcription elongation of the repeat construct. When transcription is impeded either by shutting off the promoter or by using a premature transcription terminator, hyperRecombination between repeats is abolished, providing new evidence that transcription-elongation impairment may be a source of recombinogenic substrates in mitosis. We show that Thp1p and two other proteins previously shown to control transcription-associated Recombination, Hpr1p and Tho2p, act in the same "pathway" connecting transcription elongation with the incidence of Mitotic Recombination.
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a protein complex containing tho2 hpr1 mft1 and a novel protein thp2 connects transcription elongation with Mitotic Recombination in saccharomyces cerevisiae
The EMBO Journal, 2000Co-Authors: Sebastian Chavez, Ana G Rondon, Traude H Beilharz, Hediye Erdjumentbromage, Paul Tempst, Jesper Q Svejstrup, Trevor Lithgow, Andres AguileraAbstract:Transcription‐induced Recombination has been reported in all organisms from bacteria to mammals. We have shown previously that the yeast genes HPR1 and THO2 may be keys to the understanding of transcription‐associated Recombination, as they both affect transcription elongation and hyper‐Recombination in a concerted manner. Using a yeast strain that has the wild‐type THO2 gene replaced by one encoding a His 6 ‐HA‐tagged version, we have isolated an oligomeric complex containing four proteins: Tho2, Hpr1, Mft1 and a novel protein that we have named Thp2. We have reciprocally identified a complex containing Hpr1, Tho2 and Mft1 using anti‐Mft1 antibodies in immunoprecipitation experiments. The protein complex is mainly nuclear; therefore, Tho2 and Hpr1 are physically associated. Like hpr1Δ and tho2Δ cells, mft1Δ and thp2Δ cells show Mitotic hyper‐ Recombination and impaired transcription elongation, in particular, through the bacterial lacZ sequence. Hyper‐Recombination conferred by mft1Δ and thp2Δ is only observed in DNA regions under transcription conditions. We propose that this protein complex acts as a functional unit connecting transcription elongation with the incidence of Mitotic Recombination.
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Mitotic Recombination in yeast elements controlling its incidence
Yeast, 2000Co-Authors: Andres Aguilera, Sebastian Chavez, Francisco MalagonAbstract:Mitotic Recombination is an important mechanism of DNA repair in eukaryotic cells. Given the redundancy of the eukaryotic genomes and the presence of repeated DNA sequences, Recombination may also be an important source of genomic instability. Here we review the data, mainly from the budding yeast S. cerevisiae, that may help to understand the spontaneous origin of Mitotic Recombination and the different elements that may control its occurrence. We cover those observations suggesting a putative role of replication defects and DNA damage, including double-strand breaks, as sources of Mitotic homologous Recombination. An important part of the review is devoted to the experimental evidence suggesting that transcription and chromatin structure are important factors modulating the incidence of Mitotic Recombination. This is of great relevance in order to identify the causes and risk factors of genomic instability in eukaryotes. Copyright © 2000 John Wiley & Sons, Ltd.
Allan Bradley - One of the best experts on this subject based on the ideXlab platform.
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induced Mitotic Recombination of p53 in vivo
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Wei Wang, Madhuri Warren, Allan BradleyAbstract:Genetic mosaics produced by FLP/FRT induced Mitotic Recombination have been widely used in Drosophila to study gene function in development. Recently, the Cre/loxP system has been applied to induce Mitotic Recombination in mouse embryonic stem cells and in many adult mouse tissues. We have used this strategy to generate a previously undescribed p53 mouse model in which expression of a ubiquitously expressed recombinase in a heterozygous p53 knockout animal produces Mitotic recombinant clones homozygous for the p53 mutation. The induction of loss of heterozygosity in a few cells in an otherwise normal tissue mimics genetic aspects of tumorigenesis more closely than existing models and has revealed the possible cell autonomous nature of Wnt3. Our results suggest that inducible Mitotic Recombination can be used for clonal analysis of mutants in the mouse.
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induced Mitotic Recombination a switch in time
Nature Genetics, 2002Co-Authors: David J Adams, Allan BradleyAbstract:It makes sense that our genome has evolved to have two copies of every gene—just in case something goes wrong, you still have a spare. But from the perspective of a geneticist, a diploid genome makes finding causative genes somewhat of a challenge, or at best, time consuming. One solution may be induced Mitotic Recombination.
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cancer predisposition caused by elevated Mitotic Recombination in bloom mice
Nature Genetics, 2000Co-Authors: Guangbin Luo, Allan Bradley, Irma M Santoro, Lisa D Mcdaniel, Ichiko Nishijima, Michael Mills, Hagop Youssoufian, Hannes Vogel, Roger A SchultzAbstract:Bloom syndrome is a disorder associated with genomic instability that causes affected people to be prone to cancer. Bloom cell lines show increased sister chromatid exchange, yet are proficient in the repair of various DNA lesions. The underlying cause of this disease are mutations in a gene encoding a RECQ DNA helicase. Using embryonic stem cell technology, we have generated viable Bloom mice that are prone to a wide variety of cancers. Cell lines from these mice show elevations in the rates of Mitotic Recombination. We demonstrate that the increased rate of loss of heterozygosity (LOH) resulting from Mitotic Recombination in vivo constitutes the underlying mechanism causing tumour susceptibility in these mice.