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At least 199 records · Page 11Linked to original sources
PubMed2005

Impaired genomic stability and increased oxidative stress exacerbate different features of Ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is a multisystem, cancer-predisposing genetic disorder caused by deficiency of the ATM protein. To dissect the A-T phenotype, we augmented specific features of the human disease by generating mouse strains that combine Atm deficiency with dysfunction of other proteins. Increasing oxidative stress by combining deficiencies in Atm and superoxide dismutase 1 (Sod1) exacerbated growth retardation and markedly reduced the mean survival time following ionizing radiation. In contrast, increasing genomic instability by combining deficiencies of Atm and the mismatch repair protein Mlh1 caused a moderate increase in radiation sensitivity and dramatic increase in aggressive lymphomas, compared with thes Atm-/- single knockout. Remarkably, Atm, Mlh1 or Mlh1/Atm single or double heterozygosity did not significantly affect the life span of the various genotypes. Mlh1/Atm double null tumors were polyclonal, whereas the tumors in other genotypes were mono- or oligoclonal, demonstrating the high predisposition of thymocytes with this genotype to become malignant. Chromosomal aberrations in the tumors were localized mainly in chromosomes 12 and 15. The genomic region on chromosome 15, which contains the gene for the c-Myc oncoprotein, was commonly amplified, and elevated levels of the c-Myc protein were subsequently observed in the tumors. Our data suggest that impaired genomic instability is an important contributing factor to cancer predisposition in A-T, whereas oxidative stress is more important in the radiation sensitivity and growth retardation facets of this disease.

Animals↗
PubMed2004

Genomic stability in Arabidopsis thaliana transgenic plants obtained by floral dip.

The occurrence of DNA modification is an undesired phenomenon accompanying plant cell transformation. The event has been correlated with the stress imposed by the presently utilised transformation procedures, all depending on plant differentiation from in vitro cell culture, but other causes have not been excluded. In this work, transgenic Arabidopsis thaliana plants have been produced by an approach that does not require cell dedifferentiation, being based on in planta Agrobacterium-mediated gene transfer by flower infiltration, which is followed by recovery and selection of transgenic progeny. Genomic DNA changes in transgenic and control plants have been investigated by AFLP and RAMP analysis. Results show no statistically relevant genomic modifications in transgenic plants, as compared with control untreated plants. Variations were observed in callus-derived A. thaliana plants, thus supporting the conclusion that somaclonal variation is essentially correlated with the stress imposed by the in vitro cell culture, rather than with the integration of a foreign gene.

Animals↗
PubMed2001

Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development.

DNA ligase IV (Lig4) and the DNA-dependent protein kinase (DNA-PK) function in nonhomologous end joining (NHEJ). However, although Lig4 deficiency causes late embryonic lethality, deficiency in DNA-PK subunits (Ku70, Ku80, and DNA-PKcs) does not. Here we demonstrate that, similar to p53 deficiency, ataxia-telangiectasia-mutated (ATM) gene deficiency rescues the embryonic lethality and neuronal apoptosis, but not impaired lymphocyte development, associated with Lig4 deficiency. However, in contrast to p53 deficiency, ATM deficiency enhances deleterious effects of Lig4 deficiency on growth potential of embryonic fibroblasts (MEFs) and genomic instability in both MEFs and cultured progenitor lymphocytes, demonstrating significant differences in the interplay of p53 vs. ATM with respect to NHEJ. Finally, in dramatic contrast to effects on Lig4 deficiency, ATM deficiency causes early embryonic lethality in Ku- or DNA-PKcs-deficient mice, providing evidence for an NHEJ-independent role for the DNA-PK holoenzyme.

Animals↗
PubMed2003

Telomerase alone extends the replicative life span of human skeletal muscle cells without compromising genomic stability.

Continuous cycles of muscle fiber necrosis and regeneration are characteristic of the muscular dystrophies, and in some cases this leads to premature replicative senescence of myoblasts in vitro. The molecular mechanism of senescence in human myoblasts is poorly understood but there is evidence to suggest that telomeric attrition may be one of the ways by which this is achieved. We report here, for the first time, the extension of normal human skeletal muscle cell replicative life span by the reconstitution of telomerase activity. The telomerase-expressing cells show no features of transformation in vitro and have stable genomes with diploid karyotypes, do not express exceptionally high levels of c-myc and have wild-type, unmethylated CDKN2A genes. In vivo, they regenerate to repair muscle injury in immunosuppressed RAG-1 mice. This work suggests that telomerase expression to repair short telomeres may aid the expansion of diploid human muscle cells and consequently attempts at gene therapy for muscle diseases.

Adult↗
PubMed2000

[Effect of inactivating the p33ING1 tumor suppressor on the function of cell cycle "checkpoints" and genome stability].

Novel candidate tumor suppressor p33ING1 is known to regulate activity of the p53 protein. The effect of p33ING1 inactivation on the functioning of the cell cycle "checkpoints" and the frequency of chromosomal aberrations was examined. Transduction of the p33-GSEas genetic suppressor element, known to reduce the p53 activity, into p53-positive rat and human cells resulted in: (1) partial abolishment of ethylmetansulphonate- or colcemid-induced arrest of the G1-to-S transition in the G0-synchronized cultures; (2) abolishment of the block in the S phase by the DNA synthesis inhibitor, N-phosphonacetil-L-aspartate (PALA); (3) an increase of the number of spontaneous chromosomal breaks and sister-chromatid exchanges; (4) increased frequency of colchicine-induced polyploidy. Similar effects were observed upon transduction of the p53-GSE22 genetic suppressor element, known to reduce p53 transcriptional activity. Presumably, the effect of p33ING1 inactivation on the cell cycle checkpoints and genetic stability is associated with a decrease in p53 activity.

Animals↗
PubMed2005

Roles of the Bloom's syndrome helicase in the maintenance of genome stability.

The RecQ family of DNA helicases is highly conserved in evolution from bacteria to humans. Of the five known human RecQ family members, three (BLM, WRN and RECQ4, which cause Bloom's syndrome, Werner's syndrome and Rothmund-Thomson syndrome respectively) are mutated in distinct clinical disorders associated with cancer predisposition and/or premature aging. BLM forms part of a multienzyme complex including topoisomerase IIIalpha, replication protein A and a newly identified factor called BLAP75. Together, these proteins play a role in the resolution of DNA structures that arise during the process of homologous recombination repair. In the absence of BLM, cells show genomic instability and a high incidence of sister-chromatid exchanges. In addition to a DNA structure-specific helicase activity, BLM also catalyses Holliday-junction branch migration and the annealing of complementary single-stranded DNA molecules.

Adenosine Triphosphatases↗
PubMed2005

Genomic stability and tumorigenesis.

Cancer research needs to explain the observed incidence of cancer. Many factors determine this process, including: the number of susceptible cells in the tissue of origin; the number of normal cell divisions through which susceptible cells pass in normal development and turnover; the number of cell divisions during tumorigenesis; the selective advantage which tumour cells have acquired; the ease of detection of a cancer; the number of mutations which are required for malignancy; the possible stepwise nature of tumorigenesis; the value of the normal mutation rate; the presence of extrinsic factors such as mutagens or growth promoters; the presence and strength of genomic instability, a phenomenon which has received a great deal of attention. We know very little about most of the factors and their influence in humans. We cannot, therefore, readily answer the question as to whether or not the observed incidence of cancer is what we would expect. Specifically, it is not yet possible to assess whether or not genomic instability is a prerequisite for carcinogenesis. Mathematical models, which assess the importance of genomic instability in tumorigenesis can be helpful, but require interpretation in the context of our overall ignorance. Experimental data have shown genomic instability in some cancers, but we do not yet know whether or not hypermutation initiates and drives tumorigenesis.

Cell Transformation, Neoplastic↗
PubMed2001

Copper and genomic stability in mammals.

As the free ion and in the form of some complexes, there is no doubt that copper can promote damage to cellular molecules and structures through radical formation. At the same time, and perhaps as a consequence, mammals have evolved means of minimizing levels of free copper ions and destructive copper complexes that enter the organism and its cells. These means include tight binding of copper ions to protein carriers and transporters; direct exchange of copper between protein carriers, transporters, and cuproenzymes; and mobilization of secretory mechanisms and excretory pathways, as needed. As a consequence, normally, and except under certain genetic conditions, copper is likely to be benign to most mammals and not responsible for genomic instability, including fragmentation of and/or alterations to DNA, induction of mutations or apoptosis, or other toxic events. Indeed, cuproenzymes are important members of the antioxidant system of the organism.

Animals↗
PubMed2005

Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes.

To obtain the large amount of T cells required for adoptive immunotherapy in a clinical setting, T-cell lifespan extension by human telomerase reverse transcriptase (hTERT) transduction is of particular interest. However, constitutive expression of hTERT is associated with malignant transformation and thus warrants a detailed evaluation of the safety of hTERT-transduced T cells before clinical application. In view of this, we performed an extensive cytogenetic analysis of hTERT-transduced MART-1 (melanoma antigen recognized by T cell 1)-and human papillomavirus type 16 (HPV16) E7-specific human CD8+ cytotoxic T lymphocytes (CTLs), reactive against melanoma and cervical carcinoma, respectively. Our results, obtained by (spectral) karyotyping and array comparative genomic hybridization, showed the development of minor chromosomal aberrations in an hTERT-transduced MART-1-specific CTL clone, whereas severe clonal aberrations were detected in an hTERT-transduced HPV16 E7-specific CTL clone. Furthermore, hTERT transduction did not protect CTLs from immunosenescence, because the HPV16 E7-specific, hTERT-transduced CTL clone showed a decreased functional activity on prolonged culture. Although the general frequency of major chromosomal aberrations in hTERT-transduced CTLs and the in vivo significance of our observations remain still unclear at this point, the currently available data suggest that clinical application of hTERT-transduced CTLs should proceed with caution.

CD8-Positive T-Lymphocytes↗
PubMed2006

DNA damage-dependent cell cycle checkpoints and genomic stability.

In response to genotoxic stress, which can be caused by environmental or endogenous genotoxic insults such as ionizing or ultraviolet radiation, various chemicals and reactive cellular metabolites, cell cycle checkpoints which slow down or arrest cell cycle progression can be activated, allowing the cell to repair or prevent the transmission of damaged or incompletely replicated chromosomes. Checkpoint machineries can also initiate pathways leading to apoptosis and the removal of a damaged cell from a tissue. The balance between cell cycle arrest and damage repair on one hand and the initiation of cell death, on the other hand, could determine if cellular or DNA damage is compatible with cell survival or requires cell elimination by apoptosis. Defects in these processes may lead to hypersensitivity to cellular stress, and susceptibility to DNA damage, genomic defects, and resistance to apoptosis, which characterize cancer cells. In this article, we have noted recent studies of DNA damage-dependent cell cycle checkpoints, which may be significant in preventing genomic instability.

Animals↗
PubMed2001

Vitamin D and genomic stability.

1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] has been shown to act on novel target tissues not related to calcium homeostasis. There have been reports characterizing 1,25(OH)(2)D(3) receptors and activities in diverse tissues such as brain, pancreas, pituitary, skin, muscle, placenta, immune cells and parathyroid. The receptor hormone complex becomes localized in the nucleus, and undergoes phosphorylation by reacting with a kinase. This form of the receptor then interacts with the Vitamin D responsive element of target gene and modifies the transcription of those genes to develop the action. The modulation of gene transcription results in either the induction or repression of specific messenger RNAs (m-RNAs), ultimately resulting in changes in protein expression needed to produce biological responses. Genes for carbonic anhydrase that are expressed at high levels in osteoclast are known to be involved in bone resorption and Id genes role in osteoblast-osteoclast differentiation reflects the genomic effect of Vitamin D on bones. Genomic action of Vitamin D also explains the biosynthesis of oncogenes, polyamines, lymphokines and calcium binding proteins. However, there is a possibility that some of the actions of 1,25(OH)(2)D(3) may be mediated by non-genomic mechanisms and may not require the binding to Vitamin D receptor (VDR). Vitamin D offers a protection from genotoxic effects of Vitamin D deficiency by increasing the insulin receptor gene expression and BSP (bone sialoprotein), bone-remodeling by decreasing the osteopontin (OPN) m-RNAs, maintaining the normal epidermal structure and enamel matrix. Gonadal insufficiency in Vitamin D deficiency was corrected by vitamin mediated direct regulation of the expression of aramotase gene. The supportive role of Vitamin D in placental function is also evident by its influence on human placental lactogen (hpl) gene transcription accompanied by increase hpl m-RNA levels. Further role of Vitamin D is envisaged in identifying cyclin C as an important target for Vitamin D in cell-cycle regulation. Vitamin D at physiological concentration has been found to protect cell proteins and membranes against oxidative stress by inhibiting the peroxidative attack on membrane lipids. Vitamin D, at a concentration range of 2x10(-8)-5x10(-8)M, induces apoptosis in most cancer cells, stabilizes chromosomal structure and prevents DNA double-strand breaks induced either by endogenous or exogenous factors. Vitamin D is also effective in stimulating DNA synthesis in adult alveolar II cells and provides a novel mechanism of modulation of epithelial cell proliferation in the context of lung development and repair against injury. The regulation of various proto-oncogenes (c-myc, c-fos, c-jun), differentiation inducing properties, antiproliferative effects on keratinocytes and inhibitory effects in several human malignancy ranks Vitamin D as a novel hormone that may have physiological and clinical implication in the carcinogenic process.

Animals↗
PubMed2000

Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development.

XRCC4 is a non-homologous end-joining protein employed in DNA double strand break repair and in V(D)J recombination. In mice, XRCC4-deficiency causes a pleiotropic phenotype, which includes embryonic lethality and massive neuronal apoptosis. When DNA damage is not repaired, activation of the cell cycle checkpoint protein p53 can lead to apoptosis. Here we show that p53-deficiency rescues several aspects of the XRCC4-deficient phenotype, including embryonic lethality, neuronal apoptosis, and impaired cellular proliferation. However, there was no significant rescue of impaired V(D)J recombination or lymphocyte development. Although p53-deficiency allowed postnatal survival of XRCC4-deficient mice, they routinely succumbed to pro-B-cell lymphomas which had chromosomal translocations linking amplified c-myc oncogene and IgH locus sequences. Moreover, even XRCC4-deficient embryonic fibroblasts exhibited marked genomic instability including chromosomal translocations. Our findings support a crucial role for the non-homologous end-joining pathway as a caretaker of the mammalian genome, a role required both for normal development and for suppression of tumours.

Animals↗
PubMed2003

Eme1 is involved in DNA damage processing and maintenance of genomic stability in mammalian cells.

Yeast and human Eme1 protein, in complex with Mus81, constitute an endonuclease that cleaves branched DNA structures, especially those arising during stalled DNA replication. We identified mouse Eme1, and show that it interacts with Mus81 to form a complex that preferentially cleaves 3'-flap structures and replication forks rather than Holliday junctions in vitro. We demonstrate that Eme1-/- embryonic stem (ES) cells are hypersensitive to the DNA cross-linking agents mitomycin C and cisplatin, but only mildly sensitive to ionizing radiation, UV radiation and hydroxyurea treatment. Mammalian Eme1 is not required for the resolution of DNA intermediates that arise during homologous recombination processes such as gene targeting, gene conversion and sister chromatid exchange (SCE). Unlike Blm-deficient ES cells, increased SCE was seen only following induced DNA damage in Eme1-deficient cells. Most importantly, Eme1 deficiency led to spontaneous genomic instability. These results reveal that mammalian Eme1 plays a key role in DNA repair and the maintenance of genome integrity.

Amino Acid Sequence↗
PubMed2006

BRCA2 in mitotic exit: a new role in regulating genomic stability.

Evaluation of: Daniels MJ, Wang Y, Lee M, Venkitaraman AR: Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science 306, 876-879 (2004). Cytokinesis is the division of the cytoplasm of a parent cell into daughter cells after nuclear division. Cytokinesis failure is often accompanied by the generation of cells with an unstable tetraploidy content, which predisposes the cells to develop aneuploidy and malignancies. A recent study by Venkitaraman's group demonstrates that BRCA2, a breast cancer susceptibility gene product, also functions in mediating normal cytokinesis. Similar to the subcellular localization of Aurora kinase, BRCA2 is present at the cleavage furrow and the midbody during late mitosis. Deficiency in BRCA2 function results in cytokinesis failure, which is associated with abnormal localization of myosin II, a key protein essential for the formation of the cleavage furrow. This study is of significance as it shows for the first time that BRCA2 has a function in controlling mitotic exit, deregulation of which contributes to gross genomic instabilities in daughter cells.

Animals↗
PubMed2006

Radiation-induced transgenerational alterations in genome stability and DNA damage.

Mutation induction in directly exposed cells is currently regarded as the main component of the genetic risk of ionizing radiation for humans. However, recent data on the transgenerational increases in mutation rates in the offspring of irradiated parents indicate that the genetic risk could be greater than predicted previously. Here, we have analysed transgenerational changes in mutation rates and DNA damage in the germline and somatic tissues of non-exposed first-generation offspring of irradiated inbred male CBA/Ca and BALB/c mice. Mutation rates at an expanded simple tandem repeat DNA locus and a protein-coding gene (hprt) were significantly elevated in both the germline (sperm) and somatic tissues of all the offspring of irradiated males. The transgenerational changes in mutation rates were attributed to the presence of a persistent subset of endogenous DNA lesions (double- and single-strand breaks), measured by the phosphorylated form of histone H2AX (gamma-H2AX) and alkaline Comet assays. Such remarkable transgenerational destabilization of the F(1) genome may have important implications for cancer aetiology and genetic risk estimates. Our data also provide important clues on the still unknown mechanisms of radiation-induced genomic instability.

Animals↗
PubMed2004

A model for CDK2 in maintaining genomic stability.

Abundant CDK2/cyclin A activity is present in human cancer cells, suggesting that rapid S phase CDK2 inhibition would be an effective anti-cancer approach. The dynamic change of chromatin-loading and -dissociation of MCM proteins requires S phase CDK2 activity. CDK2 inhibition during replication leads to increased MCM complex association with DNA and triggers rereplication. Overreplication-induced DSB and RPA-ssDNA intermediates activate ATM and ATR, resulting in a p53 response which selectively deletes cells with unresolved rereplication.

Antineoplastic Agents↗
PubMed1997

PARP is important for genomic stability but dispensable in apoptosis.

Mice lacking the gene encoding poly(ADP-ribosyl) transferase (PARP or ADPRT) display no phenotypic abnormalities, although aged mice are susceptible to epidermal hyperplasia and obesity in a mixed genetic background. Whereas embryonic fibroblasts lacking PARP exhibit normal DNA excision repair, they grow more slowly in vitro. Here we investigated the putative roles of PARP in cell proliferation, cell death, radiosensitivity, and DNA recombination, as well as chromosomal stability. We show that the proliferation deficiency in vitro and in vivo is most likely caused by a hypersensitive response to environmental stress. Although PARP is specifically cleaved during apoptosis, cells lacking this molecule apoptosed normally in response to treatment with anti-Fas, tumor neurosis factor alpha, gamma-irradiation, and dexamethasone, indicating that PARP is dispensable in apoptosis and that PARP-/- thymocytes are not hypersensitive to ionizing radiation. Furthermore, the capacity of mutant cells to carry out immunoglobulin class switching and V(D)J recombination is normal. Finally, primary PARP mutant fibroblasts and splenocytes exhibited an elevated frequency of spontaneous sister chromatid exchanges and elevated micronuclei formation after treatment with genotoxic agents, establishing an important role for PARP in the maintenance of genomic integrity.

Animals↗
PubMed2006

Circadian tempo: a paradigm for genome stability?

Circadian clocks are molecular time-keeping systems that underlie daily biological rhythms in anticipation of the changing light and dark cycles. These clocks mediate daily rhythms in physiology and behavior that are thought to confer an adaptive advantage for organisms. It is hypothesized that cell cycle checkpoints are gated to an intrinsic circadian clock to protect DNA from diurnal exposure to mutagens (e.g.; UV radiation peaks with daylight and dissolved genotoxins that fluctuate with feeding periods). It is proposed that DNA replication arrest in response to genotoxic stress is a likely basis for the evolution of circadian-gated DNA replication. This protective mechanism is highly conserved and can be traced along the evolutionary time-line to the early prokaryotes, unicellular eukaryotes and viruses. Peak DNA repair capacity is normally synchronous to the crest of mutagenic stress as they oscillate with respect to time. Mutator phenotypes with increased vulnerability to genotoxic stress may therefore develop when the circadian pattern of cell cycle control, DNA repair or apoptotic response are phase-shifted relative to the rhythm of mutagenic stress. The accumulating mutations would lead to accelerated aging, genome instability and neoplasia. The proposed model delineates areas of research with potentially profound implications for carcinogenesis.

Aging↗