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Results for “Genomic instability”

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At least 145 records · Page 8Linked to original sources
PubMed1999

Association of p53 genomic instability with the glutathione S-transferase null genotype in gastric cancer in the Portuguese population.

AIMS: p53 gene mutations are the most common genetic changes known to occur in human cancer. In previous studies, the presence of alterations to the p53 gene has been linked to the null phenotype of the glutathione S-transferase mu gene (GSTM1). GSTM1 appears to be part of a protective mechanism against the development of cancers in which environmental chemical carcinogens are involved. To screen for such an association in stomach cancer, p53 allelic loss and genomic instability and GSTM1 genotypes were investigated in gastric tumour DNA samples from 113 patients. METHODS: The polymerase chain (PCR) reaction was used to amplify a (CA) repeat array in the p53 locus; electrophoresis, genotyping, and allele quantification were performed using an automated DNA sequencer and Genescan software. The presence of the GSTM1 gene was determined by means of a differential PCR in which multiple genes were co-amplified in the same reaction tube. RESULTS: Loss of heterozygosity (LOH) of the p53 gene was found in 36 of 87 informative cases and genomic instability was present in eight of 113 cases. Further analysis into histological subtypes and sites of tumours did not show any positive association with p53 loss. An association between the presence of LOH and the GSTM1 null genotype was not seen; however, all the samples with genomic instability of the p53 gene (eight of 113) also showed a GSTM1 null genotype. CONCLUSION: This study does not support the hypothesis of an association between LOH in the p53 gene and the GSTM1 null genotype, but suggests that the GSTM1 null genotype might influence p53 genomic instability.

Alleles↗
PubMed2006

Radiation-induced genomic instability is associated with DNA methylation changes in cultured human keratinocytes.

The mechanism by which radiation-induced genomic instability is initiated, propagated and effected is currently under intense scrutiny. We have investigated the potential role of altered genomic methylation patterns in the cellular response to irradiation and have found evidence for widespread dysregulation of CpG methylation persisting up to 20 population doublings post-irradiation. Similar effects are seen with cells treated with medium from irradiated cells (the 'bystander effect') rather than subjected to direct irradiation. Using an arbitrarily primed methylation sensitive PCR screening method we have demonstrated that irradiation causes reproducible alterations in the methylation profile of a human keratinocyte cell line, HPV-G, and have further characterised one of these sequences as being a member of a retrotransposon element derived sequence family on chromosome 7; MLT1A. Multiple changes were also detected in the screen, which indicate that although the response of cells is predominantly hypermethylation, specific hypomethylation occurs as well. Sequence specific changes are also reported in the methylation of the pericentromeric SAT2 satellite sequence. This is the first demonstration that irradiation results in the induction of heritable methylation changes in mammalian cells, and provides a link between the various non-radiological instigators of genomic instability, the perpetuation of the unstable state and several of its manifestations.

Base Sequence↗
PubMed1998

Telomeric repeats on small polydisperse circular DNA (spcDNA) and genomic instability.

Small polydisperse circular DNA (spcDNA) is a heterogeneous population of extrachromosomal circular molecules present in a large variety of eukaryotic cells. Elevated amounts of total spcDNA are related to endogenous and induced genomic instability in rodent and human cells. We suggested spcDNA as a novel marker for genomic instability, and speculated that spcDNA might serve as a mutator. In this study, we examine the presence of telomeric sequences on spcDNA. We report for the first time the appearance of telomeric repeats in spcDNA molecules (tel-spcDNA) in rodent and human cells. Restriction enzyme analysis indicates that tel-spcDNA molecules harbor mostly, if not exclusively, telomeric repeats. In rodent cells, tel-spcDNA levels are higher in transformed than in normal cells and are enhanced by treatment with carcinogen. Tel-spcDNA is also detected in some human tumors and cell lines, but not in others. We suggest, that its levels in human cells may be primarily related to the amount of the chromosomal telomeric sequences. Tel-spcDNA may serve as a unique mutator, through specific mechanisms related to the telomeric repeats, which distinguish it from the total heterogeneous spcDNA population. It may affect telomere dynamics and genomic instability by clastogenic events, alterations of telomere size and sequestration of telomeric proteins.

Animals↗
PubMedDate not supplied

[About the peculiar form of radiation induced genome instability].

The usually studied forms of the induced genome instability manifested as a steady change of mutability of proliferated cells, we compared with its peculiar form characterized by the inherited irreversible increase of the level of spontaneous damage of cells. These effects appear of the moment of reaching of the dose threshold according to the "all or nothing" principle, just after the relatively low-dose radiational action. These changes occur without association with the cell division and thereby have an exclusive significance in the pathogenesis of the radiational damage of low-renewing mammalian tissues. It is suggested that the considered changes could underlie the development of the delayed non-cancerogenic somatic postradiational sequelae and of the acceleration of natural aging.

Aging↗
PubMed2006

[Genomic instability in the offspring of irradiated parents: facts and interpretations].

This review is devoted to genomic instability in the offspring of parents that were irradiated or treated with chemical mutagens. The evidence is presented, showing high frequency of cancer diseases and instability of the genome of somatic and germline cells in the offspring of radiation-exposed animals. Possible epigenetic mechanisms of these effects are considered, as well as their significance as components of genetic factors of radiation risk for humans.

Animals↗
PubMed2005

A mutation in the centriole-associated protein centrin causes genomic instability via increased chromosome loss in Chlamydomonas reinhardtii.

BACKGROUND: The role of centrioles in mitotic spindle function remains unclear. One approach to investigate mitotic centriole function is to ask whether mutation of centriole-associated proteins can cause genomic instability. RESULTS: We addressed the role of the centriole-associated EF-hand protein centrin in genomic stability using a Chlamydomonas reinhardtii centrin mutant that forms acentriolar bipolar spindles and lacks the centrin-based rhizoplast structures that join centrioles to the nucleus. Using a genetic assay for loss of heterozygosity, we found that this centrin mutant showed increased genomic instability compared to wild-type cells, and we determined that the increase in genomic instability was due to a 100-fold increase in chromosome loss rates compared to wild type. Live cell imaging reveals an increased rate in cell death during G1 in haploid cells that is consistent with an elevated rate of chromosome loss, and analysis of cell death versus centriole copy number argues against a role for multipolar spindles in this process. CONCLUSION: The increased chromosome loss rates observed in a centrin mutant that forms acentriolar spindles suggests a role for centrin protein, and possibly centrioles, in mitotic fidelity.

Animals↗
PubMedDate not supplied

[The long-term effects of the radiation action and induced genome instability].

The intensive studies of the long-term effects of the radiation on human and animal cells allowed to reveal the row of new positions in the radiobiology and the genetics. One of the example is the determination of the fact that the genetic effects of the radiation action are not limited by the alterations detectable directly after the corresponding influences. It was found that this and other genome alterations (the chromosome and the gene mutations, transformation the reproductive cell death, the changes of the radiosensitivity and others) can appear de novo in it's sufficiently remote generations of the surviving cells. They differ in the spectrum and in the intensity from acute influence results and now unite with notion "induced genome instability". These discoveries made the studies of the regularities and of the mechanisms of forming of the genome instability in the whole organism of the human and animals more active. In this review about radiation induced instability of genome data are systematized in the accordance with the objects of the study: cultivated cells in vitro-->posterity of laboratory animals-->children born from irradiated parents-->adult people in the remote periods after irradiation.

Animals↗
PubMed1998

Radiation-induced genomic instability in haemopoietic cells.

PURPOSE: To review studies of radiation-induced genomic instability in haemopoietic cells. MAJOR FINDINGS: Studies have demonstrated a high frequency of non-clonal, cytogenetic abnormalities in the clonal descendants of alpha-particle-irradiated (approximately one track per cell) primary murine and human haemopoietic stem cells in vitro. The induction of this phenomenon has a strong dependence on the genetic characteristics of the cells and is transmissible in vivo following transplantation of alpha-irradiated mouse bone marrow. In clonogenic cell cultures of alpha-irradiated haemopoietic cells, there is also an increased incidence of hprt mutations and an increased incidence of apoptosis. These effects may be regarded as the consequences of a destabilization of the genome collectively termed radiation-induced genomic instability. Instability is induced at very high frequencies suggesting that epigenetic changes may be a common underlying mechanism. Consistent with this suggestion is the finding of an enhanced and persisting oxy-radical activity in the descendants of irradiated stem cells, which is consistent with oxidative stress being an important feature of the mechanism(s) underlying the persistence of instability in haemopoietic cells. Recent studies have revealed that more clonogenic cells than are actually traversed by an alpha-particle are able to express the instability phenotype. These data are consistent with unexpected interactions between irradiated and non-irradiated cells but the mechanism of initiation of instability is not understood.

Alpha Particles↗
PubMed2004

Genomic instability and cancer: scanning the Caenorhabditis elegans genome for tumor suppressors.

Maintaining the stability of the genome is critical to normal cell growth and development. The early notion that cancer is the result of mutations in genes controlling cellular growth implied that gene or genome integrity is vital to the prevention of oncogenesis, and many genes and pathways that prevent genomic deterioration have been identified over the past decades. Recent progress in reverse genetic approaches, principally RNA interference, now allows the systematic analysis of gene function on a genomic scale in an animal system. Here, we discuss genomic approaches in the model organism Caenorhabditis elegans, aimed to identify genes and genetic networks that contribute to genome stability and are thus potentially involved in human carcinogenesis.

Animals↗
PubMed1994

The human Ha-ras oncogene induces genomic instability in murine fibroblasts within one cell cycle.

Many human tumors contain an activating mutation in one of the ras protooncogenes. Additionally, these tumor cells are often heteroploid and characterized by chromosome breaks and rearrangements that are consequences of the genomic instability that is thought to contribute to tumor progression. The concurrence of ras mutations and genomic instability in tumors prompted us to ask whether selective induction of an activated Ha-ras gene could render a genome unstable. The NIH 3T3 cells used in this study contained mutant p53 genes and carried a selectively inducible activated (EJ) Ha-ras transgene under the control of bacterial lactose regulatory elements. When stably transfected cells were induced to express activated Ha-ras by isopropyl beta-D-thiogalactoside administration, there was a marked increase in the number of gross chromosomal aberrations including acentric fragments, multicentric chromosomes, and double minutes, which occurred within the time frame of a single cell cycle from the time of induction. To confirm that these aberrations occurred within the first cell cycle after mutant Ha-ras induction, the cells were arrested in G1 phase by serum depletion and, subsequently, released by administration of isopropyl beta-D-thiogalactoside or serum. The mitoses from cells released with isopropyl beta-D-thiogalactoside contained a 3-fold elevation in the fraction of chromosomes containing aberrations compared to mitoses from parallel cell cultures that were released with serum. Thus, the induction of activated Ha-ras gene expression in these cells results in genomic instability that can be detected as aberrant chromosomes at the next mitosis.

3T3 Cells↗
PubMed1998

Lack of specificity of chromosome breaks resulting from radiation-induced genomic instability in Chinese hamster cells.

In V79 Chinese hamster cells, radiation-induced genomic instability results in a persistently increased frequency of micronuclei, dicentric chromosomes and apoptosis and in decreased colony-forming ability. These manifestations of radiation-induced genomic instability may be attributed to an increased rate of chromosome breakage events many generations after irradiation. This chromosomal instability does not seem to be a property which has been inflicted on individual chromosomes at the time of irradiation. Rather, it appears to be secondary to an increased level of non-specific clastogenic factors in the progeny of most if not all irradiated cells. This conclusion is drawn from the observations presented here, that all the chromosomes in surviving V79 cells are involved in the formation of dicentric chromosome aberrations 1 or 2 weeks after irradiation with about equal probability if corrections are made for chromosome length.

Animals↗
PubMed2003

Telomere dysfunction and the initiation of genome instability.

Tumour growth is an evolutionary process that is characterized by the selection of clonal populations of cells that acquire distinct genetic changes. Many cancer therapies aim to exploit the specific changes that occur in cancer cells, but understanding the underlying mechanisms of genomic instability that cause these mutations could lead to more effective therapies. If common mechanisms exist for initiating genomic instability in tumours, selection could explain the differences in specific gene mutations that accumulate in different tumour types. The cause of genomic instability in human tumours is unclear, although there is evidence to indicate that telomere dysfunction could make an important contribution.

Cellular Senescence↗
PubMed2005

MSH2 missense mutations alter cisplatin cytotoxicity and promote cisplatin-induced genome instability.

Defects in the mismatch repair protein MSH2 cause tolerance to DNA damage. We report how cancer-derived and polymorphic MSH2 missense mutations affect cisplatin cytotoxicity. The chemotolerance phenotype was compared with the mutator phenotype in a yeast model system. MSH2 missense mutations display a strikingly different effect on cell death and genome instability. A mutator phenotype does not predict chemotolerance or vice versa. MSH2 mutations that were identified in tumors (Y109C) or as genetic variations (L402F) promote tolerance to cisplatin, but leave the initial mutation rate of cells unaltered. A secondary increase in the mutation rate is observed after cisplatin exposure in these strains. The mutation spectrum of cisplatin-resistant mutators identifies persistent cisplatin adduction as the cause for this acquired genome instability. Our results demonstrate that MSH2 missense mutations that were identified in tumors or as polymorphic variations can cause increased cisplatin tolerance independent of an initial mutator phenotype. Cisplatin exposure promotes drug-induced genome instability. From a mechanistical standpoint, these data demonstrate functional separation between MSH2-dependent cisplatin cytotoxicity and repair. From a clinical standpoint, these data provide valuable information on the consequences of point mutations for the success of chemotherapy and the risk for secondary carcinogenesis.

Amino Acid Sequence↗
PubMed2006

Transgenerational transmission of radiation damage: genomic instability and congenital malformation.

The congenital malformation gastroschisis has a genetic disposition in the inbred mouse strain HLG/Zte. It is increased after preconceptional irradiation of males or females. Radiation exposures during the meiotic stages are most efficient. This malformation can also be induced by ionising radiation when the exposure takes place during the preimplantation period especially during the zygote stage. This latter effect can be transmitted to the next mouse generation. Other macroscopically visible or skeletal malformations are not significantly induced under these experimental conditions. These latter malformations are increased by radiation exposures during major organogenesis. The mechanisms for the development of the effects are different. Radiation exposure of the mouse zygote (1 to 3 hours p.c.) also leads to the induction of genomic instability in skin fibroblasts of the fetus. This phenomenon also occurs in a mouse strain (C57BL/6J) which is not susceptible to radiation-induced gastroschisis during the preimplantation period. The genomic instability is transmitted to the next mouse generation. During genomic instability chromatide breaks are dominating as in non-exposed cells. With respect to "spontaneous" malformations gastroschisis is dominating in HLG/Zte mice. Late radiation effects seem to have similar patterns as observed in non-exposed subjects, however, the rates are increased after irradiation.

Abnormalities, Radiation-Induced↗
PubMed1999

C-myc overexpression and p53 loss cooperate to promote genomic instability.

p53 monitors genomic integrity at the G1 and G2/M cell cycle checkpoints. Cells lacking p53 may show gene amplification as well as the polyploidy or aneuploidy typical of many tumors. The pathways through which this develops, however, are not well defined. We demonstrate here that the combination of p53 inactivation and c-myc overexpression in diploid cells markedly accelerates the spontaneous development of tetraploidy. This is not seen with either N-myc or L-myc. Tetraploidy is accompanied by significantly higher levels of cyclin B and its associated cdc2 kinase activity. Mitotic spindle poisons accelerate the appearance of tetraploidy in cells either lacking functional p53 or overexpressing c-myc whereas the combination is additive. Restoration of p53 function in cells overexpressing c-myc causing rapid apoptosis, indicating that cells yet to become tetraploid have nonetheless suffered irreversible genomic and/or mitotic spindle damage. In the face of normal p53 function, such damage would either be repaired or trigger apoptotis. We propose that loss of p53 and overexpression of c-myc permits the emergence and survival of cells with increasingly severe damage and the eventual development of tetraploidy.

Animals↗
PubMed1995

Mutations of the transforming growth factor-beta type II receptor gene and genomic instability in hereditary nonpolyposis colorectal cancer.

To determine the relation between the mutation of the TGF-beta type II receptor gene and genomic instability in the tumorigenesis of hereditary nonpolyposis colorectal cancer (HNPCC), we screened genomic DNA of 38 tumors from 25 HNPCC patients, 15 colorectal cancers from familial adenomatous polyposis patients, and 8 sporadic endometrial cancers, in two areas containing a (A)10 repeat or a (GT)3 repeat of the gene. Seventeen of the 24 (71%) genomic instability-positive HNPCC tumors carried one or two A deletions in the (A)10 repeat, while none of the 14 genomic instability-negative tumors did. These deletions inactivate the receptor through a frameshift mutation and the resultant protein truncation. No mutation was detected in the (GT)3 repeat sequence, but we found a missense mutation of codon 537 in the same area in one tumor. One A deletion was also detected in a genomic instability-positive sporadic endometrial cancer, but none in familial adenomatous polyposis tumors. No mutations were detected in the corresponding normal cells of these cases, indicating a somatic mutation. These data suggest that the TGF-beta type II receptor gene is a major target of genomic instability in HNPCC tumorigenesis.

Base Sequence↗
PubMed2003

Radiation-induced genomic instability and bystander effects: inter-related nontargeted effects of exposure to ionizing radiation.

The paradigm of genetic alterations being restricted to direct DNA damage after exposure to ionizing radiation has been challenged by observations in which cells that are not exposed to ionizing radiation exhibit responses typically associated with direct radiation exposure. These effects are demonstrated in cells that are the descendants of irradiated cells (radiation-induced genomic instability) or in cells that are in contact with irradiated cells or receive certain signals from irradiated cells (radiation-induced bystander effects). There is accumulating evidence that radiation-induced genomic instability may be a consequence of, and in some cell systems may also produce, bystander interactions involving intercellular signalling, production of cytokines and free-radical generation. These processes are also features of inflammatory responses that are known to have the potential for both bystander-mediated and persisting damage as well as for conferring a predisposition to malignancy. Thus, radiation-induced genomic instability and untargeted bystander effects may reflect inter-related aspects of inflammatory-type responses to radiation-induced stress and injury and contribute to the variety of pathological consequences of radiation exposures.

Animals↗
PubMed2005

Uncoupling of genomic instability and tumorigenesis in a mouse model of Burkitt's lymphoma expressing a conditional box II-deleted Myc protein.

Burkitt's lymphomas (BL) are characterized by the constitutive expression of c-Myc protein. In total, 50-60% of all BL cells carry mutant c-Myc proteins. Using a mouse model of spontaneously immortalized pro-B-lymphocytes (Ba/F3), we have investigated genomic instability mediated by the conditional expression of either wild-type (WT) or deletion box II Delta106-Myc proteins. We found that both proteins mediate common as well as differing types of chromosomal rearrangements as documented by spectral karyotyping (SKY). A higher level of genomic instability is induced by the Delta106-Myc protein. To examine the tumorigenic potential of WT or Delta106-driven Ba/F3 cells, in vivo tumorigenesis studies were performed in SCID mice. Under the experimental conditions of this study, WT but not Delta106-Myc expressing Ba/F3 cells triggered tumorigenesis in SCID mice. Therefore, the genomic instability phenotype induced by Delta106-Myc can be genetically uncoupled from its tumorigenic potential.

Animals↗