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PubMed2001

Poly(APD-ribosyl)ation, a DNA damage-driven protein modification and regulator of genomic instability.

Activation of poly(ADP-ribose) polymerase-1 (PARP-1) is an immediate cellular reaction to DNA strand breakage as induced by alkylating agents, ionizing radiation or oxidants. The resulting formation of protein-coupled poly(ADP-ribose) facilitates survival of proliferating cells under conditions of DNA damage, probably via its contribution to DNA base-excision repair. Furthermore, based on recent results there is a role emerging for PARP-1 as a negative regulator of genomic instability in cells under genotoxic stress. Regarding possible applications for clinical cancer therapy with DNA-damaging agents, it appears that both inhibition and up-regulation of the poly(ADP-ribosyl)ation response in the malignant cells to be eradicated are promising strategies to improve the outcome of such therapy, albeit for different reasons.

Animals↗
PubMedDate not supplied

Genomic instability: first step to carcinogenesis.

Multiple genetic alterations are commonly observed in human cancers. It has been suggested that inactivation of DNA repair pathways, which leads to an increased mutation rate and chromosomal instability, can initiate and accelerate the neoplastic process. Such a causality has been shown for DNA mismatch repair and Hereditary Nonpolyposis Colorectal Cancer (HNPCC), and evidence is accumulating that several other DNA repair pathways are frequently inactivated in different cancer types. In addition to genetic alterations, perturbations in DNA methylation patterns (epigenetic changes), which include both local hypermethylation and genome-wide hypomethylation, are frequently observed early in tumorigenesis. Therefore, genomic instability including genetic and/or epigenetic alterations may be the first step in carcinogenesis. Knowledge of these biochemical mechanisms are likely to lead to more effective cancer diagnosis and therapy.

Cell Transformation, Neoplastic↗
PubMed2002

Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX.

In mammalian cells, DNA double-strand breaks (DSBs) cause rapid phosphorylation of the H2AX core histone variant (to form gamma-H2AX) in megabase chromatin domains flanking sites of DNA damage. To investigate the role of H2AX in mammalian cells, we generated H2AX-deficient (H2AX(Delta)/Delta) mouse embryonic stem (ES) cells. H2AX(Delta)/Delta ES cells are viable. However, they are highly sensitive to ionizing radiation (IR) and exhibit elevated levels of spontaneous and IR-induced genomic instability. Notably, H2AX is not required for NHEJ per se because H2AX(Delta)/Delta ES cells support normal levels and fidelity of V(D)J recombination in transient assays and also support lymphocyte development in vivo. However, H2AX(Delta)/Delta ES cells exhibit altered IR-induced BRCA1 focus formation. Our findings indicate that H2AX function is essential for mammalian DNA repair and genomic stability.

Amino Acid Sequence↗
PubMed1999

Genomic instability, DNA methylation, and natural selection in colorectal carcinogenesis.

Neoplastic transformation is increasingly understood in terms of evolutionary mechanisms, and it is now widely accepted that tumor progression involves natural selection of genetic variants occurring in the somatic environment. Here we give a review of data that substantiate this Darwinian view to tumorigenesis, with particular emphasis on recent advances related to colorectal cancer. We specifically focus on the controversies related to genomic instability and DNA methylation, and present a model, which interrelates these phenomena to the basic evolutionary concept of biology.

Cell Transformation, Neoplastic↗
PubMed1996

Analysis of genomic instability in Li-Fraumeni fibroblasts with germline p53 mutations.

Germline p53 mutations are frequently observed in the normal DNA of cancer-prone patients with Li-Fraumeni syndrome (LFS). Fibroblasts from LFS patients develop chromosomal aberrations, loss of cell cycle control, and spontaneous immortalization. We transfected four different mutant p53 genes into human skin fibroblasts from normal donors with two copies of wild-type p53 (p53(wt/wt)). Each mutant p53 expression-plasmid induced genomic instability equivalent to that seen in LFS cells. To test the role of wild-type and mutant p53 alleles in DNA replication and fidelity in LFS cells, we analysed the replication of the SV40-based shuttle vector pZ189 in four types of cells. We used p53(wt/mut) and p53(mut/-) LFS fibroblasts, and p53(-/-) non-LFS cells. Replication of pZ189 in vivo was significantly reduced by the presence of a p53(wt) allele. To show that this was not just due to inhibition of the function of T-antigen in SV40-based replication, we constructed a shuttle vector, pZ402, that contains a mutation in SV40 T-antigen which blocks its ability to interact with p53. Replication of pZ402 in LFS cells was also reduced by the presence of p53(wt), indicating that p53 can inhibit replication by interacting with proteins within the cellular replication machinery. Replicative errors in this shuttle vector are detected as mutations in a marker gene, supF. In addition to supF mutations, we observed deletion of a portion of the SV40 T-antigen gene in 100% of replicated plasmid pZ189 mutants (supF-) from the p53(wt/mut) fibroblasts and in 88% of the supF mutants from the p53(mut/-) (amino acid 175 arg to his) LFS cells. In one cell strain of immortal LFS cells, P53(mut/-) , containing a p53 frameshift mutation at amino acid 184, pZ189 replication yielded very few of these deleted shuttle vector plasmids (15%). These large deletions were not detected in plasmids replicated in p53(-/-) non-LFS cells, Saos-2 cells. Replicated plasmids with a normal supF gene were never found to have this large deletion regardless of the cell from which they were derived. Because the supF gene is not in the same region of the shuttle vector as the T-antigen gene it appears that second, independent gene deletions are frequent when replicative errors in supF occur in cells with a mutant p53. We conclude, therefore, that p53(wt/mut) LFS cells contain an activity that promotes mutations. Such an activity, which is likely to be due to the p53(mut), could result in the high rate of chromosomal instability and allelic loss of the wild-type p53 observed as these cells spontaneously immortalize.

Alleles↗
PubMed2001

Extracellular signaling through the microenvironment: a hypothesis relating carcinogenesis, bystander effects, and genomic instability.

Cell growth, differentiation and death are directed in large part by extracellular signaling through the interactions of cells with other cells and with the extracellular matrix; these interactions are in turn modulated by cytokines and growth factors, i.e. the microenvironment. Here we discuss the idea that extracellular signaling integrates multicellular damage responses that are important deterrents to the development of cancer through mechanisms that eliminate abnormal cells and inhibit neoplastic behavior. As an example, we discuss the action of transforming growth factor beta (TGFB1) as an extracellular sensor of damage. We propose that radiation-induced bystander effects and genomic instability are, respectively, positive and negative manifestations of this homeostatic process. Bystander effects exhibited predominantly after a low-dose or a nonhomogeneous radiation exposure are extracellular signaling pathways that modulate cellular repair and death programs. Persistent disruption of extracellular signaling after exposure to relatively high doses of ionizing radiation may lead to the accumulation of aberrant cells that are genomically unstable. Understanding radiation effects in terms of coordinated multicellular responses that affect decisions regarding the fate of a cell may necessitate re-evaluation of radiation dose and risk concepts and provide avenues for intervention.

Bystander Effect↗
PubMed2003

Human syndromes with genomic instability and multiprotein machines that repair DNA double-strand breaks.

The present report deals with the functional relationships among protein complexes which, when mutated, are responsible for four human syndromes displaying cancer proneness, and whose cells are deficient in DNA double-strand break (DSB) repair. In some of them, the cells are also unable to activate the proper checkpoint, while in the others an unduly override of the checkpoint-induced arrest occurs. As a consequence, all these patients display genome instability. In ataxia-telangiectasia, the mutated protein (ATM) is a kinase, which acts as a transducer of DNA damage signalling. The defective protein in the ataxia-telangiectasia-like disorder is a DNase (the Mre11 nuclease) that in vivo produces single-strand tails at both sides of DSBs. Mre11 is always present with the Rad50 ATPase in a protein machine: the nuclease complex. In mammals, this complex also contains nibrin, the protein mutated in the Nijmegen syndrome. Nibrin confers new abilities to the nuclease complex, and can also bind to BRCA1 (one of the two proteins mutated in familial breast cancer). BRCA1 has a central motif that binds with high affinity to cruciform DNA, a structure present in places where the DNA loops are anchored to the chromosomal axis or scaffold. The BRCA1 x cruciform DNA complex should be released to allow the nuclease complex to work in DNA recombinational repair of DSBs. BRCA1 also acts as a scaffold for the assembly of ATPases such as Rad51, responsible for the somatic homologous recombination. Loss of the BRCA1 gene prevents cell survival after exposure to cross-linkers. The BRCA1-RING domain is an E3-ubiquitin ligase. It can mono-ubiquitinate the FANCD2 protein, mutated in one of the Fanconi anemia complementation groups, to regulate it. Finally, during DNA replication, the nuclease complex and its activating ATM kinase are integrated in the BRCA1-associated surveillance complex (BASC) that contains, among others, enzymes required for mismatch excision repair. In short, the proteins missing in these syndromes have in common their BRCA1-mediated assembly into multimeric machines responsible for the surveillance of DNA replication, DSB recombinational repair, and the removal of DNA cross-links.

Apoptosis↗
PubMed2001

Attenuation of radiation-induced genomic instability by free radical scavengers and cellular proliferation.

To investigate the mechanisms of radiation-induced chromosomal instability, cells were irradiated in the presence of the free radical scavengers DMSO, glycerol, or cysteamine, in the presence of DMSO while frozen, or held in confluence arrest post-irradiation to permit cells to repair potentially lethal DNA damage. Clones derived from single progenitor cells surviving each treatment were then analyzed for the subsequent development of chromosomal instability. The presence of scavengers (+/- freezing) during irradiation, and the recovery from potentially lethal damage after irradiation led to an increase in cell survival that was accompanied by a decrease in the initial yield of chromosomal rearrangements. Furthermore, analysis of over 400 clones and 80,000 metaphases indicates that these same treatments reduced the incidence of instability at equitoxic doses when compared to controls irradiated in the absence of scavengers at ambient temperature. Results suggest that preventing reactive species from damaging DNA, promoting chemical repair of ionized DNA intermediates, or allowing enzymatic removal of genetic lesions, represent measures that reduce the total burden of DNA damage and reduce the subsequent onset of radiation-induced genomic instability.

Animals↗
PubMed2003

Non-targeted and delayed effects of exposure to ionizing radiation: II. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects.

The goal of this review is to summarize the evidence for non-targeted and delayed effects of exposure to ionizing radiation in vivo. Currently, human health risks associated with radiation exposures are based primarily on the assumption that the detrimental effects of radiation occur in irradiated cells. Over the years a number of non-targeted effects of radiation exposure in vivo have been described that challenge this concept. These include radiation-induced genomic instability, bystander effects, clastogenic factors produced in plasma from irradiated individuals that can cause chromosomal damage when cultured with nonirradiated cells, and transgenerational effects of parental irradiation that can manifest in the progeny. These effects pose new challenges to evaluating the risk(s) associated with radiation exposure and understanding radiation-induced carcinogenesis.

Animals↗
PubMedDate not supplied

Genomic instability, bystander effects and radiation risks: implications for development of protection strategies for man and the environment.

The last few years has seen what people are now referring to as a "shifting Paradigm" in our way of thinking about radiation effects on biological systems. The concept of the central role of DNA damage due to double strand breaks induced by a radiation "hit" has been itself hit by many studies showing persistent effects in the distant progeny of radiation exposed cells. This phenomenon is known as radiation induced genomic instability. More recently evidence has been accumulating that not even the parent cell need be exposed to radiation (the bystander effect). The new paradigm suggests that cellular stress responses or damage signalling through a range of signal transduction pathways are involved and that cell-cell contact or secretion of damage signalling molecules can induce responses in undamaged and unirradiated cells. Are these new effects relevant to risk assessment, or does it matter HOW radiation affects cells if we have good epidemiological evidence of which to base our risk estimates? The aim of this paper is to introduce the new concepts and to consider reasons why they might alter our methods of risk estimation. The paper also considers the impact of the new concepts on environmental protection and discusses the need for research in the field of comparative radiobiology if we are to develop policies which can adequately protect biodiversity.

Animals↗
PubMed1998

Genomic instability associated with myotonic dystrophy does not involve p53 expression and activity.

We tested the hypothesis that the instability of the trinucleotide CTG at the myotonic dystrophy (DM) locus could be an intrinsic DNA damage recognisable by the p53 cell-cycle checkpoint system. p53 mRNA and protein levels were assayed in muscle biopsies and fibroblast cell lines of DM patients and unaffected controls. No differences in mRNA and protein levels were found between patients and controls, regardless of their expansion size. However, in the cells treated with adryamicin, p53 protein levels were comparable in DM and control cells. We conclude that the CTG trinucleotide expansion within the myotonin gene does not activate the p53 surveillance system, at least in adult tissues. The escape of trinucleotide expansion from the p53-mediated DNA repair system could explain some of the biological characteristics of genome instability.

Adult↗
PubMed1997

The yeast HPR1 gene has a functional role in transcriptional elongation that uncovers a novel source of genome instability.

The yeast HPR1 gene plays an important role in genome stability, as indicated by the observation that hpr1 mutants have high frequencies of DNA repeat recombination and chromosome loss. Here we report that HPR1 is required for transcriptional elongation. Transcription driven from constitutive and regulated yeast promoters cannot elongate through the bacterial lacZ coding region in hpr1Delta cells, but progresses efficiently through other sequences such as yeast PHO5. We show that HPR1 is not required for transcription activation and that the previously reported effects of hpr1Delta on the activation of different promoters is a consequence of the incapacity of hpr1Delta cells to elongate transcription through lacZ, used as reporter. Transcriptional defects are also observed in yeast DNA sequences of hpr1Delta cells in the presence of the transcription elongation inhibitor 6-azauracil. In all cases, the blockage of transcription elongation in hpr1Delta is associated with both the high frequency of deletions and the increase in plasmid instability that we report here. Therefore, in addition to the identification of a new element involved in transcriptional elongation, our work provides evidence for a new source of genomic instability.

Chromosome Deletion↗
PubMed1995

Radiation-induced carcinogenesis: individual sensitivity and genomic instability.

In spite of a well-known relationship between exposure to radiation and increased risk for cancer development, the biological mechanisms involved in radiation-induced carcinogenesis remain poorly documented. Various hypotheses are discussed in this paper. It appears that radiation cannot be directly responsible for the numerous genetic alterations of cancer cells. Most of them occur during tumor progression. Only one or a very limited number of them was induced by radiation many years before tumor growth. This long delay is a major difficulty for experimental research and raises many questions. Recently, it has been shown that a genomic instability occurs after many generations in cells descending from irradiated cells. This instability leads to multiple genetic alterations and, preferentially, affects some chromosome structures, particularly telomeres. This kind of telomeric instability - related to the shortening of telomeric DNA sequences - has also been observed in senescent cells as well as in non-senescent cells from patients predisposed to cancer, and this process may possibly also occur in the progeny of irradiated cells.

Animals↗
PubMed2001

Genomic instability in cancer.

Solid tumours have abnormal, deficient vascular and lymphatic systems. As a result, perfusion within these malignancies is inadequate and chaotic, and the cancers contain regions that are transiently and chronically exposed to low pH, severe hypoxia and nutrient deprivation. These microenvironmental inadequacies are present from the earliest point in the development of solid tumours, and are fully established while the neoplasms are still microscopic. Exposures to acidic and hypoxic environments have been shown to produce a wide range of cytogenetic changes. These include increases in mutation frequencies; deficits in DNA repair; DNA overreplication and gene amplification; the induction of chromosomal fragile sites, triggering genomic rearrangements; and changes in gene expression. Moreover, exposure of cells to adverse microenvironments such as those in solid tumours selects for cells which have defects in the structure or expression of the genes that normally regulate cell proliferation. The genetic changes and selection pressures induced by hypoxia may be critical in causing the development of the genomic instability and genetic heterogeneity which is characteristic of solid tumours and in fostering the evolution of relatively benign cell populations in solid tumours to increasingly malignant, increasingly aggressive phenotypes.

Cell Hypoxia↗
PubMed1995

Genomic instability and the role of p53 mutations in cancer cells.

The p53 tumor-suppressor gene encodes a cell-cycle checkpoint protein that functions in the G1 phase of the cell cycle. When DNA damage is incurred, p53 transactivates a number of downstream genes whose products, with diverse biologic activities, each make a contribution to the cellular response to DNA damage. One major p53-mediated stress response is the G1 cell-cycle arrest, or delay, which probably allows the cell time to repair DNA damage prior to S-phase entry. In cells lacking p53 function, which include most cancer cells, a condition of genomic instability results from checkpoint loss that culminates in gene amplifications, aneuploidy, and other chromosomal aberrations. These abnormalities contribute to the clonal evolution of cancer cells and tumor progression. The role of p53 in radioresistance and chemoresistance is discussed.

Animals↗
PubMed1999

Lethal and teratogenic effects in two successive generations of the HLG mouse strain after radiation exposure of zygotes -- association with genomic instability?

We analysed the transmission of lethal and teratogenic events to the subsequent generation in HLG/Zte mice after exposure of the zygote stage to 1 Gy X-rays. As observed in previous studies, our results on teratogenic events occurring in the same generation, which was exposed during the zygote stage, reveal a significantly higher risk for the induction of gastroschisis. Interesting new insights came from the study of lethal and teratogenic effects in the generation obtained after mating female mice, which were exposed during their zygote stage, to unexposed males. An approximately 2-fold higher level of damage was manifest in this generation compared with controls, expressed mainly as a significant increase of prenatal mortality (P<0.01). Although there was an increase in the number of malformed fetuses on day 19 of gestation (6.5% cases of gastroschisis compared to 3.5% in the controls), the frequency of gastroschisis in the exposed group was just not statistically significant (P>0.05). These results are in line with the hypothesis that genomic instability is involved in the damage seen after radiation exposure of the zygote stage of HLG mice.

Animals↗
PubMed1998

Manifestations and mechanisms of radiation-induced genomic instability in V-79 Chinese hamster cells.

PURPOSE: The relationship between different forms of persistent radiation damage in irradiated cells was investigated in order to identify a common underlying mechanism. MATERIAL AND METHODS: V-79 Chinese hamster cells were irradiated with different doses of X-rays, neutrons and alpha-particles. In the progeny of surviving cells, up to 4 weeks after irradiation, delayed reproductive death, delayed micronuclei, delayed appearance of dicentric chromosomes and delayed apoptosis were investigated in parallel. RESULTS: A similar dose-response relationship was found for all endpoints, with a steep rise at low doses to a plateau at doses > 3 Gy. The target for inducing genomic instability by alpha-particles is larger than the nucleus. All chromosomes are equally involved in delayed breakage reunion events. CONCLUSION: The results indicate that non-lethal radiation damage to an extranuclear target leads to a persistent increase in clastogenic activity in the surviving irradiated cells.

Alpha Particles↗
PubMed1999

Effect of 0.2 T static magnetic field on human neurons: remodeling and inhibition of signal transduction without genome instability.

We describe the effect of the static magnetic field generated by a 0.2 T magnetic resonance tomograph on a normal human neuronal cell culture (FNC-B4). After 15 min exposure cells showed dramatic changes of morphology: they formed vortexes of cells and exposed branched neurites featuring synaptic buttons. At the same time, thymidine incorporation and inositol lipid signaling were significantly reduced. Control (sham exposed) or non-neuronal cells (mouse leukemia, and human breast carcinoma cells) did not show any alteration following exposure. Endothelin-1 release from FNC-B4 cells was also dramatically reduced after 5 min exposure. However, PCR analysis of 12 DNA microsatellites selected as gauges of genome instability, did not reveal any alteration following exposure, thus ruling out a direct effect of the magnetic field on DNA stability. These data can be interpreted as a specific effect of the static magnetic field on human neuronal cells and are consistent with the induction of remodeling and differentiation; they demonstrate that fields below 0.5 T have significant biological effects on human neurons.

Cell Line↗