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At least 397 records · Page 22Linked to original sources
PubMed1997

Lethal mutations and genomic instability.

The delayed expression of cell death in progeny of irradiated survivors was christened 'lethal mutations' by Tikvah Alper in 1984. The effect occurs when clones, or populations of cells grown up from irradiated progenitor cells, are replated and reassessed for cloning efficiency or population doubling time. The effect has been shown to be associated with the low dose shoulder region of the survival curve and is due to events occurring in the first two hours post irradiation, i.e. the 'fast repair' period. In this review the lethal mutation data accumulated over the past ten years is discussed in relation to our modern understanding of cellular and molecular events in radiation carcinogenesis and genomic instability research. It is suggested that lethal mutations are associated with a general epigenetic or field effect occurring in all irradiated cells, which makes them more prone to mutations, some of which are lethal. The implications of this for our current approach to risk estimates and therapeutic dose calculation, need to be addressed.

Animals↗
PubMed1998

Tumors of DNA mismatch repair-deficient hosts exhibit dramatic increases in genomic instability.

DNA mismatch repair (MMR) deficiency is associated with an increased mutational burden and predisposition to certain malignancies. Relatively little is known, however, about gene-specific mutation frequencies within MMR-deficient primary tumors. Thymic lymphomas from Msh2(-/-) mice were thus analyzed by using a lacI-based transgenic shuttle-phage mutation detection system. All tumors exhibited greatly elevated lacI gene mutation frequencies, ranging from 3.2- to 17.4-fold above the approximately 15-fold elevations present within normal Msh2(-/-) thymi. In addition, lacI genes harboring multiple changes, including clusters of mutations, were found in thymic tumor DNA. The results suggest that an additional mutator activity, such as an error-prone DNA polymerase, leads to increased genomic instability in these MMR-deficient tumors.

Animals↗
PubMed2000

Sequential chromosome aberration analysis following radiotherapy - no evidence for enhanced genomic instability.

Chromosome analysis of peripheral blood lymphocytes using block staining was performed on 18 cancer patients who had received fractionated radiotherapy doses totalling 35-80 Gy. Samples were obtained from 13 individuals within 1 year of treatment and thereafter approximately annually up to a maximum of eight times (range: three to eight samples per individual). Sampling of the remaining five patients started later. Frequencies of cells with unstable chromosome aberrations showed a steady decline whereas frequencies of cells with just chromatid aberrations and gaps were initially low and remained so. There was no subsequent rise in any aberrant cell type in later years and thus no suggestion that the radiation exposure had induced a persistent or late manifesting state of genomic instability.

Adult↗
PubMed1992

Anoxia-inducible endonuclease activity as a potential basis of the genomic instability of cancer cells.

Normal rat fibroblasts exhibit a staged response to anoxia which in several respects parallels processes activated in malignant tumor cells. We describe here a new element of the anoxic response, the induction by anoxia of a sequestered endonuclease activity. Such activity is elevated approximately 3-fold within anoxic fibroblasts and during Hirt DNA isolation is able to digest chromatin to produce a nucleosomal ladder. However, DNA is not measurably affected within intact cells, and cells retain complete viability as the endonuclease is induced. The anoxia-inducible endonuclease acts without specificity for DNA sequence. Trace leakage of this endonuclease into the nucleus has obvious potential to underlie the known propensity of anoxic cells to undergo amplification and may be associated with the break-related genomic instability of cancer cells.

Animals↗
PubMed2001

Radiation induces genomic instability and mammary ductal dysplasia in Atm heterozygous mice.

Ataxia-telangiectasia (AT) is a genetic syndrome resulting from the inheritance of two defective copies of the ATM gene that includes among its stigmata radiosensitivity and cancer susceptibility. Epidemiological studies have demonstrated that although women with a single defective copy of ATM (AT heterozygotes) appear clinically normal, they may never the less have an increased relative risk of developing breast cancer. Whether they are at increased risk for radiation-induced breast cancer from medical exposures to ionizing radiation is unknown. We have used a murine model of AT to investigate the effect of a single defective Atm allele, the murine homologue of ATM, on the susceptibility of mammary epithelial cells to radiation-induced transformation. Here we report that mammary epithelial cells from irradiated mice with one copy of Atm truncated in the PI-3 kinase domain were susceptible to radiation-induced genomic instability and generated a 10% incidence of dysplastic mammary ducts when transplanted into syngenic recipients, whereas cells from Atm(+/+) mice were stable and formed only normal ducts. Since radiation-induced ductal dysplasia is a precursor to mammary cancer, the results indicate that AT heterozygosity increases susceptibility to radiogenic breast cancer in this murine model system.

Animals↗
PubMed1998

Mechanisms and implications of genomic instability and other delayed effects of ionizing radiation exposure.

Recently there has been considerable interest in various delayed effects of radiation. These have the common property of showing a high and, in some instances, non-clonal transmission of 'damage' to distant progeny which derive from apparently normal surviving cells and their descendants. This means that conventional analysis and interpretation of long-term radiation damage in terms of mutations induced in DNA at the time of radiation exposure may be incorrect. Several reviews of this area have appeared in recent years which have described the historical development of this field. The aim of this commentary is to highlight areas of discussion, particularly concerning links between the various end-points, and to discuss some of the possible implications of genomic instability for radiation carcinogenesis in general and for the setting of radiation protection action limits in particular.

Animals↗
PubMed1994

The genomic instability associated with integrated simian virus 40 DNA is dependent on the origin of replication and early control region.

DNA rearrangements in the form of deletions and duplications are found within and near integrated simian virus 40 (SV40) DNA in nonpermissive cell lines. We have found that rearrangements also occur frequently with integrated pSV2neo plasmid DNA. pSV2neo contains the entire SV40 control region, including the origin of replication, both promoters, and the enhancer sequences. Linearized plasmid DNA was electroporated into X1, an SV40-transformed mouse cell line that expresses SV40 large T antigen (T Ag) and shows very frequent rearrangements at the SV40 locus, and into LMtk-, a spontaneously transformed mouse cell line that contains no SV40 DNA. Stability was analyzed by subcloning G-418-resistant clones and examining specific DNA fragments for alterations in size. Five independent X1 clones containing pSV2neo DNA were unstable at both the neo locus and the T Ag locus. By contrast, four X1 clones containing mutants of pSV2neo with small deletions in the SV40 core origin and three X1 clones containing a different neo plasmid lacking SV40 sequences were stable at the neo locus, although they were still unstable at the T Ag locus. Surprisingly, five independent LMtk- clones containing pSV2neo DNA were unstable at the neo locus. LMtk- clones containing origin deletion mutants were more stable but were not as stable as the X1 clones containing the same plasmid DNA. We conclude that the SV40 origin of replication and early control region are sufficient viral components for the genomic instability at sites of SV40 integration and that SV40 T Ag is not required.

Animals↗
PubMed2001

Multiple manifestations of X-ray-induced genomic instability in Chinese hamster ovary (CHO) cells.

Carcinogenesis is postulated to follow a multistep cascade in which the first genetic event may destabilize cells and thereby facilitate the induction of subsequent mutations within the same cell. It has recently been shown that exposure to ionizing radiation can in itself induce a persistent, heritable genetic instability in cells. To further investigate this phenomenon, we utilized a mutationally unstable population derived from a single Chinese hamster ovary (CHO) cell that survived X irradiation. We exposed these cells to a second dose of radiation, selected hypoxanthine phosphoribosyl transferase (HPRT) mutant subclones, and identified the type of mutations involved. We found complete deletions, continuous tract partial deletions, single-exon deletions, discontinuous-exon deletions ("skip mutations"), and point mutations (changes of less than 100 bp) among the isolated HPRT mutants. We hypothesized that the skip mutation clones might be more likely to demonstrate genomic instability. To test this hypothesis, mutant subclones were screened for three markers of genetic instability: alteration of minisatellite sequences, change in telomere length, and induction of chromosomal aberrations. Clones with skip mutations and single-exon deletions possessed elevated frequencies of minisatellite alterations and chromosomal aberrations, particularly rings and dicentrics. All mutant clones showed longer telomere terminal restriction fragment lengths than did wild-type cells. These results are consistent with the hypothesis that irradiation may induce a global instability phenotype, since the multiple alterations observed are mechanistically distinct, heritable cellular modifications that arose in the clonogenic progeny of the irradiated cells. Skip mutations may be one manifestation of this instability, but their presence was not specifically associated with the other genetic alterations.

Animals↗
PubMed1989

Progression to cancer in Barrett's esophagus is associated with genomic instability.

Barrett's esophagus is a condition in which metaplastic columnar epithelium replaces squamous esophageal epithelium as a consequence of chronic gastroesophageal reflux. Patients with this condition are at increased risk for the development of adenocarcinoma. To better understand the progression to adenocarcinoma in this disease, we studied abnormalities in DNA content of epithelial cells in Barrett's esophagus. Using flow cytometry, we examined the spatial distribution of abnormal nuclear DNA contents (aneuploidy) in the esophagi of 14 patients with Barrett's adenocarcinoma. Multiple (2 to 14) populations of aneuploid cells were seen in 12 of the 14 cases. Some early carcinomas appeared to be associated with a single aneuploid population of cells. Surrounding dysplastic epithelium often contained multiple, different overlapping aneuploid populations. These data suggest that neoplastic progression in Barret's esophagus is associated with a process of genomic instability which leads to evolution of multiple aneuploid populations, with the ultimate development of a clone of cells capable of malignant invasion. Thus, detection of multiple aneuploid populations of cells in Barrett's esophagus may indicate a high risk of cancer. Barrett's esophagus provides a unique and readily accessible model for the study of neoplastic progression in human epithelial malignancy.

Adenocarcinoma↗
PubMed2002

BCR/ABL regulates response to DNA damage: the role in resistance to genotoxic treatment and in genomic instability.

BCR/ABL regulates cell proliferation, apoptosis, differentiation and adhesion. In addition, BCR/ABL can induce resistance to cytostatic drugs and irradiation by modulation of DNA repair mechanisms, cell cycle checkpoints and Bcl-2 protein family members. Upon DNA damage BCR/ABL not only enhances reparation of DNA lesions (e.g. homologous recombination repair), but also prolongs activation of cell cycle checkpoints (e.g. G2/M) providing more time for repair of otherwise lethal lesions. Moreover, by modification of anti-apoptotic members of the Bcl-2 family (e.g. upregulation of Bcl-x(L)) BCR/ABL provides a cytoplasmic 'umbrella' protecting mitochondria from the 'rain' of apoptotic signals coming from the damaged DNA in the nucleus, thus preventing release of cytochrome c and activation of caspases. The unrepaired and/or aberrantly repaired (but not lethal) DNA lesions resulting from spontaneous and/or drug-induced damage can accumulate in BCR/ABL-transformed cells leading to genomic instability and malignant progression of the disease. Inhibition of BCR/ABL kinase activity by STI571 (Gleevec, imatinib mesylate) reverses drug resistance and, in combination with standard chemotherapeutics can exert strong anti-leukemia effect.

Antineoplastic Agents↗
PubMed2000

Poly(ADP-ribosyl)ation, genomic instability, and longevity.

Poly(ADP-ribosyl)ation is a DNA strandbreak-driven posttranslational modification of nuclear proteins that is catalyzed by poly(ADP-ribose) polymerase-1 (PARP-1), with NAD+ serving as substrate. Recently, additional PARP isoforms were described that seem to account for a minor fraction of cellular poly(ADP-ribose) synthesis. We have previously described a correlation between poly(ADP-ribosyl)ation capacity of mononuclear leukocytes of various mammalian species and species-specific life span. Likewise, lymphoblastoid cell lines derived from human centenarians display a higher poly(ADP-ribosyl)ation capacity than do controls. At the functional level, recent data show that PARP-1 is a key regulator of alkylation-induced sister-chromatid exchange, imposing a negative control commensurate with the enzyme activity. PARP-1 activity may therefore be responsible for tuning the rate of genomic instability events that are provoked by the constant attack of endogenous and exogenous genotoxins to a level appropriate for the longevity potential of a given organism or species.

Animals↗
PubMed1997

Increased tumor proliferation and genomic instability without decreased apoptosis in MMTV-ras mice deficient in p53.

We have used an in vivo tumor model to evaluate the consequences of p53 tumor suppressor protein deficiency in a tissue-specific context. By breeding MMTV-ras transgenic mice, which are highly susceptible to the development of mammary and salivary tumors, with p53(-/-) mice, we generated three classes of animals which contained the MMTV-ras transgene but differed in their p53 functional status (ras/p53(+/+), ras/p53(+/-), or ras/p53(-/-)). ras/p53(-/-) mice developed tumors more rapidly than animals of the other two genotypes; however, the distribution of tumors was unexpectedly altered. Whereas the most frequently observed tumors in ras/p53(+/+) and ras/p53(+/-) mice were of mammary origin, ras/p53(-/-) mice developed primarily salivary tumors. In addition, the mammary and salivary tumors from ras/p53(-/-) mice consistently exhibited a number of unfavorable characteristics, including higher histologic grades, increased growth rates, and extensive genomic instability and heterogeneity, relative to tumors from ras/p53(+/+) mice. Interestingly, the increased growth rates of ras/p53(-/-) tumors appear to be due to impaired cell cycle regulation rather than decreased apoptosis, suggesting that p53-mediated tumor suppression can occur independent of its role in apoptosis.

Aneuploidy↗
PubMed2006

Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice.

Genetic defects in nucleotide excision repair (NER) are associated with premature aging, including cancer, in both humans and mice. To investigate the possible role of increased somatic mutation accumulation in the accelerated appearance of symptoms of aging as a consequence of NER deficiency, we crossed four different mouse mutants, Xpa-/-, Ercc6(Csb)-/-, Ercc2(Xpd)m/m and Ercc1-/m, with mice harboring lacZ-reporter genes to assess mutant frequencies and spectra in different organs during aging. The results indicate an accelerated accumulation of mutations in both liver and kidney of Xpa defective mice, which correlated with a trend towards a decreased lifespan. Until 52 weeks, Xpa deficiency resulted mainly in 1-bp deletions. At old age (104 weeks), the spectrum had undergone a shift, in both organs, to G:C-->T:A transversions, a signature mutation of oxidative DNA damage. Ercc1-/m mice, with their short lifespan of 6 months and severe symptoms of premature aging, especially in liver and kidney, displayed an even faster lacZ-mutant accumulation in liver. In this case, the excess mutations were mostly genome rearrangements. Csb-/- mice, with mild premature aging features and no reduction in lifespan, and Xpdm/m mice, exhibiting prominent premature aging features and about 20% reduction in lifespan, did not have elevated lacZ-mutant frequencies. It is concluded that while increased genomic instability could play a causal role in the mildly accelerated aging phenotype in the Xpa-null mice or in the severe progeroid symptoms of the Ercc1-mutant mice, shortened lifespan in mice with defects in transcription-related repair do not depend upon increased mutation accumulation.

Aging, Premature↗
PubMed2001

Conversion of normal to malignant phenotype: telomere shortening, telomerase activation, and genomic instability during immortalization of human oral keratinocytes.

Normal somatic cells terminate their replicative life span through a pathway leading to cellular senescence, which is triggered by activation of p53 and/or pRb in response to critically shortened telomere DNA. Potentially neoplastic cells must first overcome the senescence checkpoint mechanisms and subsequently activate telomerase to propagate indefinitely. Although telomerase activation is closely associated with cellular immortality, telomerase alone is not sufficient to warrant tumorigenicity. Environmental factors, including chemical carcinogens and viral infection, often contribute to aberrant changes leading to tumorigenic conversion of normal cells. Of particular importance in oral cancer development are tobacco-related chemical carcinogens and human papillomavirus (HPV) infection. To describe the molecular mechanisms by which these environmental factors facilitate the genesis of oral cancer, we first established an in vitro multistep oral carcinogenesis model by sequential exposure of normal human oral keratinocytes (NHOK) to "high risk" HPV and chemical carcinogens. Upon introduction of the HPV genome, the cells bypassed the senescence checkpoint and entered into an extended, but not immortal, life span during which telomere DNA continued to shorten. In a few immortal clones surviving beyond the crisis, we found a marked elevation of telomerase activity and stabilization of telomere length. Furthermore, the E6 and E7 oncoproteins of "high risk" HPV disrupted the cell cycle control and DNA repair in immortalized HOK, and enhanced mutation frequency resulting from genomic instability. However, HPV infection alone failed to give rise to a tumorigenic cell population, which required further exposure to chemical carcinogens in addition to HPV infection. Analysis of the data presented suggests that oral carcinogenesis is a series of discrete genetic alterations that result from a continued genotoxic challenge by environmental risk factors. Our in vitro model may be useful for investigators with interest in furthering our understanding of oral carcinogenesis.

Alcohol Drinking↗
PubMed1992

Interlocus V-J recombination measures genomic instability in agriculture workers at risk for lymphoid malignancies.

V(D)J [variable-(diversity)-joining] rearrangements occur between, as well as within, immune receptor loci, resulting in the generation of hybrid antigen-receptor genes and the formation of a variety of lymphocyte-specific chromosomal aberrations. Such hybrid genes occur at a low frequency in the peripheral blood lymphocytes (PBL) of normal individuals but show a markedly increased incidence in the PBL of individuals with the autosomal recessive disease ataxia-telangiectasia. In this manuscript we demonstrate that the frequency of hybrid antigen-receptor genes is 10- to 20-fold increased in the PBL of an occupational group, agriculture workers, with related environmental exposures. Both ataxia-telangiectasia patients and this population of agriculture workers are at increased risk for lymphoid malignancy. This result suggests that the measurement of hybrid antigen receptor-genes in PBL may be a sensitive assay for a type of lymphocyte-specific genomic instability. As a corollary, this assay may identify populations at risk of developing common types of lymphoid malignancy.

Agricultural Workers' Diseases↗
PubMed2001

Genomic instability, bystander effect, cytoplasmic irradiation and other phenomena that may achieve fame without fortune.

The possible risk of induced malignancies in astronauts, as a consequence of the radiation environment in space, is a factor of concern for long term missions. Cancer risk estimates for high doses of low LET radiation are available from the epidemiological studies of the A-bomb survivors. Cancer risks at lower doses cannot be detected in epidemiological studies and must be inferred by extrapolation from the high dose risks. The standard setting bodies, such as the ICRP recommend a linear, no-threshold extrapolation of risks from high to low doses, but this is controversial. A study of mechanisms of carcinogenesis may shed some light on the validity of a linear extrapolation. The multi-step nature of carcinogenesis suggests that the role of radiation may be to induce a mutation leading to a mutator phenotype. High energy Fe ions, such as those encountered in space are highly effective in inducing genomic instability. Experiments involving the single particle microbeam have demonstrated a "bystander effect", ie a biological effect in cells not themselves hit, but in close proximity to those that are, as well as the induction of mutations in cells where only the cytoplasm, and not the nucleus, have been traversed by a charged particle. These recent experiments cast doubt on the validity of a simple linear extrapolation, but the data are so far fragmentary and conflicting. More studies are necessary. While mechanistic studies cannot replace epidemiology as a source of quantitative risk estimates, they may shed some light on the shape of the dose response relationship and therefore on the limitations of a linear extrapolation to low doses.

Alpha Particles↗
PubMed1996

DNA-replication fidelity, mismatch repair and genome instability in cancer cells.

It has been suggested that an early event in the multistep progression of a normal cell to a tumor cell could be a defect that leads to an elevated mutation rate, thus providing a pool of mutants upon which selection could act to yield a tumor. Such a mutator phenotype could result from a defect in any of several DNA transactions, including those that determine the DNA replication error rate or the ability to correct replication errors. Recent evidence for the latter is the mutator phenotype observed in tumor cells of patients having a hereditary form of colon cancer. These patients have a germline mutation in genes required for post-replication DNA mismatch repair. A second mutation arises somatically, yielding a greatly elevated mutation rate due to an inability to correct DNA replication errors. This connection between cancer, DNA replication errors and defective mismatch repair is the subject of this review, wherein we consider the key steps and principles for high fidelity replication and how their perturbation results in genome instability.

Base Sequence↗
PubMed1999

Genomic instability in Schistosoma mansoni.

In schistosomes, the W chromosome characterizes the heterogametic female-sex (ZW) whereas males are homogametic (ZZ). In the heterochromatic region of the W chromosome, the repetitive elements W1 and W2 are located which had originally been found as female-specific sequences in Puerto Rican isolates of Schistosoma mansoni. An analysis of the strain- and sex-specific occurrence of these elements revealed that both elements can occur gender-independently in other Puerto Rican isolates and in a variety of other strains of S. mansoni. This result contradicted earlier findings and indicated the existence of polymorphic Z chromosomes. A genetic analysis of the occurrence of W1 and W2 in a series of clonal populations of Schistsoma mansoni is presented. Although clones of this parasite are regarded as genetically identical, striking inter- and even intra-clonal variations have been found by PCR and Southern-blot experiments with the DNA of individual clones and of the progeny of crossing experiments. The results do not support the hypothesis of polymorphic Z chromosomes. Instead, they strongly suggest genomic instability probably originating from unusual DNA recombination events at the meiotic and mitotic level. These findings suggest a further method of generating variability within schistosomes. rights reserved.

Animals↗