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PubMed2001

No evidence for chromosomal instability in radiation workers with in vivo exposure to plutonium.

The availability of cultured lymphocyte preparations from radiation workers with internal deposits of plutonium provided the opportunity to examine whether irradiation of bone marrow cells had induced a transmissible genomic instability manifesting as an increase in de novo chromosome aberrations in descendant cells in the peripheral blood. The men were originally classified as having more than 20% of the maximum permissible body burdens of plutonium, and recent red bone marrow dose calculations provided individual cumulative estimates at the time of sampling ranging up to 1.8 Sv. The initial sampling occurred approximately 10 years after the main major intake, and samples were subsequently taken during three further periods over the following 20 years. Control samples were available from three of the four sampling times. Chromosome analysis of solid Giemsa-stained material revealed no significant differences either in comparisons between the total group of plutonium workers and controls for comparable periods or when the comparisons were restricted to a group of plutonium workers with initial red bone marrow plutonium doses greater than 0.25 Sv. However, the frequencies of cells containing chromatid exchanges, chromatid breaks, and chromosome and chromatid gaps decreased significantly over the study period for both the plutonium workers as a whole and the controls, and a similar fluctuating pattern was seen when sequential samples from groups of the same individuals were examined. Cells with dicentrics, centric rings and excess acentric fragments remained at similar frequencies throughout the study period. There was therefore no evidence from the study of blood lymphocytes for the induction of persistent transmissible genomic instability in the bone marrow of radiation workers with internal deposits of plutonium. The work has, however, confirmed the need for appropriate controls when conducting studies of cytogenetic end points of instability.

Adult↗
PubMed2001

Detecting rare mutations associated with cancer risk.

For more than a decade, investigators have been searching for a means of determining the risk of individuals developing cancer by detecting rare oncogenic mutations. The accumulation of mutations and the clonal evolvement of tumors provide opportunities for monitoring disease development and intervening prior to the presentation of clinical symptoms, or determining the risk of disease relapse during remission. A number of techniques, mostly polymerase chain reaction (PCR)-based, have been developed that enable the detection of rare oncogenic mutations within the range of 10(-2) to 10(-4) wild-type cells. Only a handful of procedures enable the detection of intragenic single base mutations at one mutant in 10-6 or better. These ultra-sensitive mutation detection techniques have produced some interesting results regarding single base mutation spectra and frequencies in p53, Harvey-ras, N-ras, and other reporter genes and DNA sequences in human tissues. Although there is evidence that some individuals may harbor cells or clones expressing genomic instability, the connection with the processes of carcinogenesis is still tenuous. There remains a need for rigorous epidemiological studies employing these ultra-sensitive mutation detection procedures. Since genomic instability is considered key to tumor development, the relevance of the detection of hypermutable clones in individuals is discussed in the context of cancer risk.

Body Fluids↗
PubMed2004

Repair of radiation damage to DNA.

DNA double-strand breaks constitute the most dangerous type of DNA damage induced by ionising radiation (IR). Accordingly, the resistance of cells to IR is modulated by three intimately related cellular processes: DNA repair, recombination, and replication. Significant discoveries in this field of research have been made over the last few years. A picture seems to be emerging in which perturbations of recombination in cancer cells are a more widespread cause of genomic instability than previously appreciated. Conversely, such cells may also be more sensitive to certain chemotherapeutic drugs and to IR. Thus, the alterations in recombination that promote carcinogenesis by causing genomic instability may also be the weakness of the tumours that arise in this setting, a concept which could hold great promise for the advancement of cancer treatment in the not too distant future.

Animals↗
PubMed2006

Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs.

Ku80 maintains the genome by repairing DNA double-strand breaks (DSBs) through nonhomologous end joining (NHEJ), a pathway that repairs nonspecific DSBs and Rag-1 Rag-2 (Rag)-specific DSBs. As a result, Ku80 deletion results in phenotypes characteristic of defective repair for both nonspecific DSBs (gamma-radiation hypersensitivity and genomic instability) and Rag-specific DSBs (immunodeficiency). ku80(-/-) mice also exhibit neuronal apoptosis, but we do not know the type of DSBs responsible for this response. In spite of genomic instability and immunodeficiency, cancer incidence is not increased in ku80(-/-) mice. However, deletion of the tumor suppressor, p53 greatly increases pro-B-cell lymphoma in ku80(-/-) mice due to IgH/c-Myc translocations suggesting that responses to Rag-specific DNA DSBs suppress cancer. Like suppression of pro-B-cell lymphoma, neuronal apoptosis requires p53 presenting the intriguing possibility that Rag-specific DSBs mediate neuronal development as they do lymphocyte development. Here we delete Rag-1 from ku80(-/-)p53(-/-) mice to differentiate the impact nonspecific vs Rag-specific DSBs have on ku80(-/-) mice. We find that deleting Rag-1 prevents pro-B cell lymphoma confirming Rag-induced DSBs induce this form of cancer. Both the triple mutant mice and the p53(-/-)rag-1(-/-) mice exhibit T-cell lymphoma and medulloblastoma; incidence of T-cell lymphoma is the same for both cohorts whereas incidence of medulloblastoma is higher for the triple-mutant cohort. Thus, p53-mediated neuronal apoptosis likely suppresses medulloblastoma in Ku80-deleted mice and Ku80 likely suppresses medulloblastoma by repairing nonspecific DNA DSBs instead of Rag-specific DSBs. Our observations are the first to show that Ku80 suppresses cancer caused by nonspecific DNA damage and we present a novel mouse model for medulloblastoma.

Animals↗
PubMed2006

[DNA helicases and human diseases].

DNA helicases are molecular motors that catalyse the unwinding of energetically unstable structures into single strands and have therefore an essential role in nearly all metabolism transactions. Defects in helicase function can result in human syndromes in which predisposition to cancer and genomic instability are common features. So far different helicase genes have been found associated in 8 such disorders. RecQ helicases are a family of conserved enzymes required for maintaining the genome integrity that function as suppressors of inappropriate recombination. Mutations in RecQ4, BLM and WRN give rise to various disorders: Bloom syndrome, Rothmund-Thomson syndrome, and Werner syndrome characterized by genomic instability and increased cancer susceptibility. The DNA helicase BRIP1/BACH1 is involved in double-strand break repair and is defective in Fanconi anemia complementation group J. Mutations in XPD and XPB genes can result in xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy, three genetic disorders with different clinical features but with association of transcription and NER defects. This review summarizes our current knowledge on the diverse biological functions of these helicases and the molecular basis of the associated diseases.

Abnormalities, Multiple↗
PubMed2000

The establishment of telomerase-immortalized cell lines representing human chromosome instability syndromes.

The limited life span of normal human cells represents a substantial obstacle for biochemical analysis, genetic manipulation and genetic screens. To overcome this technical barrier, immortal human cell lines are often derived from tumors or produced by transformation with viral oncogenes such as SV40 large T antigen. Cell lines produced by these approaches are invariably transformed, genomically unstable and display cellular properties that differ from their normal counterpart. It was recently shown that the ectopic expression of hTERT, encoding the catalytic subunit of human telomerase, can extend the life span of normal human cells without causing cellular transformation and genomic instability. In the present study, we have used hTERT to extend the life span of normal human skin fibroblasts derived from patients afflicted with syndromes of genomic instability and/or premature aging. Our results show that hTERT efficiently extends the life span without altering the characteristic phenotypic properties of the cells. Thus, the ectopic expression of telomerase represents a major improvement over the use of viral oncogenes for the establishment of human cell lines.

Abnormalities, Multiple↗
PubMed2002

Genetic instability in cancer tissues analyzed by random amplified polymorphic DNA PCR.

OBJECTIVE: To detect DNA and chromosomes instabilities during the progression of tumors and screen new molecular markers coupled to putative or unknown oncogenes and/or tumor suppressor genes. METHODS: Five kinds of tumors, in a total of 128 specimens, were analyzed by random amplified polymorphic DNA (RAPD) PCR. Bands representing instabilities were recovered, purified, and cloned, labeled as probes for Southern and Northern blot analysis and DNA sequencing. RESULTS: Sample 5 and 3 of the gastric cancer tissues showed the highest genomic changes and the average detectability in five cancers was up to at least 40% (42.2% - 49.4%). There were significant differences in the ability of each primer to detect genomic instability, which ranged from 27% (primer 8) to 68% (primer 2). Band B is a single copy fragment, and was found to be an allelic loss in gastric and colon cancers. It is a novel sequence and was registered in GenBank with Accession Number AF151005. Further analysis revealed that it might be part of a cis-regulatory element of a new tumor suppressor gene, containing a promoter of cis-action "CACA" box, an enhancer of "GATA" family and a start codon. CONCLUSIONS: It was impossible or difficult to get great achievements for cancer treatments with the procedure of gene therapy only to one oncogene or one tumor suppressor gene because the extensive DNA variations occurred during the progression of tumor. RAPD assay connected with other techniques was a good tool for the detection of genomic instabilities and direct screening of some new molecular markers related to tumor suppressor genes or oncogenes.

Base Sequence↗
PubMed2006

Evidence that the S.cerevisiae Sgs1 protein facilitates recombinational repair of telomeres during senescence.

RecQ DNA helicases, including yeast Sgs1p and the human Werner and Bloom syndrome proteins, participate in telomere biology, but the underlying mechanisms are not fully understood. Here, we explore the protein sequences and genetic interactors of Sgs1p that function to slow the senescence of telomerase (tlc1) mutants. We find that the S-phase checkpoint function of Sgs1p is dispensable for preventing rapid senescence, but that Sgs1p sequences required for homologous recombination, including the helicase domain and topoisomerase III interaction domain, are essential. sgs1 and rad52 mutations are epistatic during senescence, indicating that Sgs1p participates in a RAD52-dependent recombinational pathway of telomere maintenance. Several mutations that are synthetically lethal with sgs1 mutation and which individually lead to genome instability, including mus81, srs2, rrm3, slx1 and top1, do not speed the senescence of tlc1 mutants, indicating that the rapid senescence of sgs1 tlc1 mutants is not caused by generic genome instability. However, mutations in SLX5 or SLX8, which encode proteins that function together in a complex that is required for viability in sgs1 mutants, do speed the senescence of tlc1 mutants. These observations further define roles for RecQ helicases and related proteins in telomere maintenance.

Cellular Senescence↗
PubMed2003

Folate deficiency, mismatch repair-dependent apoptosis, and human disease.

The vitamin that is most commonly deficient in the American diet is folate. Severe folate deficiency in humans is known to cause megaloblastic anemia and developmental defects, and is associated with an increased incidence of several forms of human cancer. Although the exact mechanisms by which this vitamin deficiency may cause these diseases are not known at the present time, recent work has shown that folate deficiency also causes genomic instability and programmed cell death (or apoptosis). Additionally, it is known that the DNA mismatch repair pathway mediates folate deficiency-induced apoptosis. This review will first describe work suggesting that folate deficiency causes genomic instability and apoptosis, then discuss possible mechanisms by which the mismatch repair pathway could trigger folate deficiency-induced apoptosis, which has either protective or destructive effects on tissue.

Apoptosis↗
PubMed2000

The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations.

We have used spectral karyotyping to assess potential roles of three different components of the nonhomologous DNA end-joining pathway in the maintenance of genomic stability in mouse embryonic fibroblasts (MEFs). MEFs homozygous for mutations that inactivate either DNA ligase IV (Lig4) or Ku70 display dramatic genomic instability, even in the absence of exogenous DNA damaging agents. These aberrant events range from chromosomal fragmentation to nonreciprocal translocations that can involve several chromosomes. DNA-dependent protein kinase catalytic subunit deficiency also promotes genome instability. Deficiency for the p53 cell cycle checkpoint protein has little effect on spontaneous levels of chromosomal instability in Lig4-deficient fibroblasts. However, in the context of ionizing radiation treatment, p53 deficiency allowed visualization of massive acute chromosomal destruction in Lig4-deficient MEFs, which in surviving cells manifested as frequent nonreciprocal translocations. We conclude that nonhomologous DNA end-joining plays a crucial role as a caretaker of the mammalian genome, and that an alternative repair pathway exists that often leads to nonreciprocal translocations.

Animals↗
PubMed2006

Genome-wide hypomethylation in human glioblastomas associated with specific copy number alteration, methylenetetrahydrofolate reductase allele status, and increased proliferation.

Genome-wide reduction in 5-methylcytosine is an epigenetic hallmark of human tumorigenesis. Experimentally induced hypomethylation in mice promotes genomic instability and is sufficient to initiate tumorigenesis. Here, we report that global hypomethylation is common in primary human glioblastomas [glioblastoma multiforme (GBM)] and can affect up to an estimated 10 million CpG dinucleotides per haploid tumor genome. Demethylation involves satellite 2 (Sat2) pericentromeric DNA at chromosomes 1 and 16, the subtelomeric repeat sequence D4Z4 at chromosomes 4q and 10q, and interspersed Alu elements. Severe hypomethylation of Sat2 sequences is associated with copy number alterations of the adjacent euchromatin, suggesting that hypomethylation may be one factor predisposing to specific genetic alterations commonly occurring in GBMs. An additional apparent consequence of global hypomethylation is reactivation of the cancer-testis antigen MAGEA1 via promoter demethylation, but only in GBMs and GBM cell lines exhibiting a 5-methylcytosine content below a threshold of approximately 50%. Primary GBMs with significant hypomethylation tended to be heterozygous or homozygous for the low-functioning Val allele of the rate-limiting methyl group metabolism gene methylenetetrahydrofolate reductase (MTHFR), or had a deletion encompassing this gene at 1p36. Tumors with severe genomic hypomethylation also had an elevated proliferation index and deletion of the MTHFR gene. These data suggest a model whereby either excessive cell proliferation in the context of inadequate methyl donor production from MTHFR deficiency promotes genomic hypomethylation and further genomic instability, or that MTHFR deficiency-associated demethylation leads to increased proliferative activity in GBM.

5-Methylcytosine↗
PubMed2003

Characterization of a novel epigenetic effect of ionizing radiation: the death-inducing effect.

The detrimental effects associated with exposure to ionizing radiation have long been thought to result from the direct targeting of the nucleus leading to DNA damage; however, the emergence of concepts such as radiation-induced genomic instability and bystander effects have challenged this dogma. After cellular exposure to ionizing radiation, we have isolated a number of clones of Chinese hamster-human hybrid GM10115 cells that demonstrate genomic instability as measured by chromosomal destabilization. These clones show dynamic and persistent generation of chromosomal rearrangements multiple generations after the original insult. We hypothesize that these unstable clones maintain this delayed instability phenotype by secreting factors into the culture medium. To test this hypothesis we transferred filtered medium from unstable cells to unirradiated GM10115 cells. No GM10115 cells were able to survive this medium. This phenomenon by which GM10115 cells die when cultured in medium from chromosomally unstable GM10115 clones is the death-inducing effect. Medium transfer experiments indicate that a factor or factors is/are secreted by unstable cells within 8 h of growth in fresh medium and result in cell killing within 24 h. These factors are stable at ambient temperature but do not survive heating or freezing, and are biologically active when diluted with fresh medium. We present the initial description and characterization of the death-inducing effect. This novel epigenetic effect of radiation has implications for radiation risk assessment and for health risks associated with radiation exposure.

Animals↗
PubMed2004

Mitochondria damage checkpoint in apoptosis and genome stability.

Mitochondria perform multiple cellular functions including energy production, cell proliferation and apoptosis. Studies described in this paper suggest a role for mitochondria in maintaining genomic stability. Genomic stability appears to be dependent on mitochondrial functions involved in maintenance of proper intracellular redox status, ATP-dependent transcription, DNA replication, DNA repair and DNA recombination. To further elucidate the role of mitochondria in genomic stability, I propose a mitochondria damage checkpoint (mitocheckpoint) that monitors and responds to damaged mitochondria. Mitocheckpoint can coordinate and maintain proper balance between apoptotic and anti-apoptotic signals. When mitochondria are damaged, mitocheckpoint can be activated to help cells repair damaged mitochondria, to restore normal mitochondrial function and avoid production of mitochondria-defective cells. If mitochondria are severely damaged, mitocheckpoint may not be able to repair the damage and protect cells. Such an event triggers apoptosis. If damage to mitochondria is continuous or persistent such as damage to mitochondrial DNA resulting in mutations, mitocheckpoint may fail which can lead to genomic instability and increased cell survival in yeast. In human it can cause cancer. In support of this proposal we provide evidence that mitochondrial genetic defects in both yeast and mammalian systems lead to impaired DNA repair, increased genomic instability and increased cell survival. This study reveals molecular genetic mechanisms underlying a role for mitochondria in carcinogenesis in humans.

Adenosine Triphosphate↗
PubMed2003

DNA stability and schizophrenia in twins.

The goal of these experiments was to understand DNA changes relevant to schizophrenia. This work compared DNA of monozygotic (MZ) twins surrounding (CAG)(n) repeating sequences, and characterized the relationship between fragile sites and schizophrenia. Twelve twin-pairs, previously classified as MZ and 18 unrelated sib-pairs, from seven families were studied. Eight twin-pairs were affected by schizophrenia, four concordantly and four discordantly. DNA comparisons were made using profiles of electrophoretic size fractionations of PCR amplified (CAG)(n) containing genomic fragments. These profiles were generated by a new method, developed by us, called targeted genomic differential display (TGDD). Surprisingly, the number of peak profile differences in MZ twin-pairs discordant for schizophrenia was greater than the concordantly ill twins and the well twins and, in some cases, overlapped the range of sib-pairs. These results might mean that some twins were not MZ but it was not possible to definitively test these samples for zygosity. Alternatively, the results might be explained as an increased mutation rate (or genomic instability) around (CAG)(n) sites in individuals afflicted with schizophrenia. Also, we uncovered an association of schizophrenia (i.e., a linkage of chromosomal abnormalities and gene localizations) with fragile sites spread throughout the genome (chi(2), P = 0.001). Furthermore, it appears that an increasing number of genes linked to schizophrenia are associated with (CAG)(n) sequences. Fragile sites and (CAG)(n) repeat sequences are known to be unstable. We speculate the association of genomic instability with schizophrenia accounts for seemingly disparate biological and environmental factors that influence disease occurrence.

Adolescent↗
PubMed1999

Functional analysis of human FEN1 in Saccharomyces cerevisiae and its role in genome stability.

The flap endonuclease, FEN1, is an evolutionarily conserved component of DNA replication from archaebacteria to humans. Based on in vitro results, it processes Okazaki fragments during replication and is involved in base excision repair. FEN1 removes the last primer ribonucleotide on the lagging strand and it cleaves a 5' flap that may result from strand displacement during replication or during base excision repair. Its biological importance has been revealed largely through studies in the yeast Saccharomyces cerevisiae where deletion of the homologous gene RAD27 results in genome instability and mutagen sensitivity. While the in vivo function of Rad27 has been well characterized through genetic and biochemical approaches, little is understood about the in vivo functions of human FEN1. Guided by our recent results with yeast RAD27, we explored the function of human FEN1 in yeast. We found that the human FEN1 protein complements a yeast rad27 null mutant for a variety of defects including mutagen sensitivity, genetic instability and the synthetic lethal interactions of a rad27 rad51 and a rad27 pol3-01 mutant. Furthermore, a mutant form of FEN1 lacking nuclease function exhibits dominant-negative effects on cell growth and genome instability similar to those seen with the homologous yeast rad27 mutation. This genetic impact is stronger when the human and yeast PCNA-binding domains are exchanged. These data indicate that the human FEN1 and yeast Rad27 proteins act on the same substrate in vivo. Our study defines a sensitive yeast system for the identification and characterization of mutations in FEN1.

Amino Acid Sequence↗
PubMed2004

Is there a link between DNA polymerase beta and cancer?

Recent small-scale studies have shown that 30% of human tumors examined to date express DNA polymerase beta variant proteins. One of the DNA polymerase beta colon cancer-associated mutants, K289M, has been shown to synthesize DNA with a lower fidelity than wild-type Pol beta. Thus, the K289M protein could confer a mutator phenotype to the cell, resulting in genomic instability. Another DNA polymerase beta variant identified in colon carcinoma interferes with base excision repair in cells. This may result in unfilled gaps which can serve as substrates for recombination and result in genomic instability. DNA polymerase beta has also been shown to be overexpressed in a variety of tumors. In some cases, overexpression of polymerase beta in cells confers a transformed phenotype to the cells. In other cases, overexpression results in telomere fusions. Thus, mutant forms or aberrant quantities of polymerase beta confer a mutator phenotype to cells. Combined with the small-scale tumor studies, these mechanistic studies implicate variant forms of DNA polymerase beta in the etiology of human cancer.

Amino Acid Substitution↗
PubMed2001

Niacin, poly(ADP-ribose) polymerase-1 and genomic stability.

Nicotinic acid (NA) and nicotinamide (NAM), commonly called niacin, are the dietary precursors for NAD(+) (nicotinamide adenine dinucleotide), which is required for DNA synthesis, as well as for the activity of the enzyme poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) for which NAD(+) is the sole substrate. The enzyme PARP-1 is highly activated by DNA strand breaks during the cellular genotoxic stress response, is involved in base excision repair, plays a role in p53 expression and activation, and hence, is thought to be important for genomic stability. In this review, first the absorption, metabolism of niacin to NAD(+), as well as the assessment of niacin status are discussed. Since NAD(+) is important for PARP-1 activity, various aspects of PARP-1 in relation to DNA synthesis and repair, and regulation of gene expression are addressed. This is followed by a discussion on interactions between dietary methyl donor deficiency, niacin status, PARP-1 activity and genomic stability. In vitro studies show that PARP-1 function is impaired and genomic stability decreased when cells are either depleted from NAD(+) or incubated with high concentrations of NAM which is a PARP-1 inhibitor. In vitro as well as animal studies indicate that niacin deficiency increases genomic instability especially in combination with genotoxic and oxidative stress. Niacin deficiency may also increase the risk for certain tumors. Preliminary data suggest that niacin supplementation may protect against UV-induced tumors of the skin in mice, but data on similar preventive effects in humans are not available. NAM has been shown in vitro to have an antioxidant activity comparable to that of ascorbic acid. Data on niacin status and genomic stability in vivo in humans are limited and yield ambiguous results. Therefore, no firm conclusions with respect to optimal niacin intake are possible. As a consequence of oral niacin supplementation, however, NAM levels in the body may increase, which may result in inhibition of PARP-1 and increased genomic instability. More studies are needed to define an optimal level of niacin nutriture in relation to genomic stability and tumorigenesis.

Animals↗
PubMed2002

Retinoblastoma tumor suppressor and genome stability.

Retinoblastoma gene (Rb) is the prototype of tumor suppressors. Germline mutation in the retinoblastoma gene is susceptible to cancer and reintroduction of wild-type Rb is able to suppress neoplastic phenotypes. The fundamental cellular functions of Rb in the control of cell growth and differentiation are important for its tumor suppression. In general, cancer susceptibility caused by inactivation of a tumor suppressor gene results from genome instability. Accordingly, Rb may function in the maintenance of chromosome stability by influencing mitotic progression, faithful chromosome segregation, and structural remodeling of mitotic chromosomes. Rb is also implicated in the regulation of replication machinery and in the control of cell cycle checkpoints in response to DNA damage, further supporting such a role for Rb. Moreover, the mechanistic basis for Rb-mediated transcriptional repression has revealed its connection to global chromatin remodeling. It is likely that Rb suppresses tumor formation by virtue of its multiple biological activities, and a theme throughout its multiple cellular functions is its central role in controlling activities that involve chromatin remodeling. A model in which Rb controls global genome fluidity is thus proposed. Finally, a recent study provides direct evidence indicating that loss of Rb function leads to genome instability. Therefore, tumor suppressors have a common role in the maintenance of genome stability, and such a role may be pivotal for their functions in tumor suppression.

Animals↗