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PubMed2004

Can GH induce chromosome breaks or microsatellite instability in GH-deficient children?

The role of GH in carcinogenesis is unclear. We studied the effect of recombinant human GH (rhGH) in vitro on chromosomal and genomic instability. Thirteen children, aged 9.57 +/- 1.08 yr (mean +/- SEM), with complete (no.=5) or partial (no.=8) GH deficiency were evaluated before and during GH treatment. We examined the incidence of chromosome and chromatid breaks, and microsatellite instability after in vitro addition of two different doses of rhGH to peripheral blood lymphocytes obtained from the patients. No differences were observed between the samples of GH-deficient children before and after GH therapy as regards the percentage of chromosome and chromatids breaks, and in microsatellite instability. Our data show that in vitro addition of rhGH does not induce chromosomal and/or genomic instability in cultured lymphocytes.

Cells, Cultured↗
PubMed2006

Intrinsic molecular signature of breast cancer in a population-based cohort of 412 patients.

BACKGROUND: Molecular markers and the rich biological information they contain have great potential for cancer diagnosis, prognostication and therapy prediction. So far, however, they have not superseded routine histopathology and staging criteria, partly because the few studies performed on molecular subtyping have had little validation and limited clinical characterization. METHODS: We obtained gene expression and clinical data for 412 breast cancers obtained from population-based cohorts of patients from Stockholm and Uppsala, Sweden. Using the intrinsic set of approximately 500 genes derived in the Norway/Stanford breast cancer data, we validated the existence of five molecular subtypes--basal-like, ERBB2, luminal A/B and normal-like--and characterized these subtypes extensively with the use of conventional clinical variables. RESULTS: We found an overall 77.5% concordance between the centroid prediction of the Swedish cohort by using the Norway/Stanford signature and the k-means clustering performed internally within the Swedish cohort. The highest rate of discordant assignments occurred between the luminal A and luminal B subtypes and between the luminal B and ERBB2 subtypes. The subtypes varied significantly in terms of grade (p < 0.001), p53 mutation (p < 0.001) and genomic instability (p = 0.01), but surprisingly there was little difference in lymph-node metastasis (p = 0.31). Furthermore, current users of hormone-replacement therapy were strikingly over-represented in the normal-like subgroup (p < 0.001). Separate analyses of the patients who received endocrine therapy and those who did not receive any adjuvant therapy supported the previous hypothesis that the basal-like subtype responded to adjuvant treatment, whereas the ERBB2 and luminal B subtypes were poor responders. CONCLUSION: We found that the intrinsic molecular subtypes of breast cancer are broadly present in a diverse collection of patients from a population-based cohort in Sweden. The intrinsic gene set, originally selected to reveal stable tumor characteristics, was shown to have a strong correlation with progression-related properties such as grade, p53 mutation and genomic instability.

Breast Neoplasms↗
PubMed1997

Differential induction of chromosomal instability by DNA strand-breaking agents.

To investigate the role of DNA strand breakage as the molecular lesion responsible for initiating genomic instability, five different strand-breaking agents, bleomycin, neocarzinostatin, hydrogen peroxide, restriction endonucleases, and ionizing radiation, were examined for their capacity to induce delayed chromosomal instability. These studies used GM10115 human-hamster hybrid cells, which contain one copy of human chromosome 4 in a background of 20-24 hamster chromosomes. Chromosomal instability was investigated using fluorescence in situ hybridization to visualize chromosomal rearrangements involving the human chromosome. Rearrangements are detected multiple generations after treatment, in clonal populations derived from single progenitor cells surviving treatment of the specified DNA-damaging agents. Clastogenic and cytotoxic activities of all agents were tested by examining chromosome aberration yields in first-division metaphases and by clonogenic survival assays. Analysis of over 250 individual clones representing over 50,000 metaphases demonstrates that when compared at comparable levels of cell kill, ionizing radiation, bleomycin, and neocarzinostatin are equally effective at eliciting delayed genomic instability. These observations document, for the first time, the persistent destabilization of chromosomes following chemical treatment. In contrast, the analysis of nearly 300 clones and 60,000 metaphases, involving treatment with four different restriction endonucleases and/or hydrogen peroxide, did not show any delayed chromosomal instability. These data indicate that DNA strand breakage per se does not necessarily lead to chromosomal instability but that the complexity or quality of DNA strand breaks are important in initiating this phenotype.

Adenine Phosphoribosyltransferase↗
PubMed2006

ATM is activated by mitotic stress and suppresses centrosome amplification in primary but not in tumor cells.

Centrosome amplification has been proposed to contribute to the development of aneuploidy and genome instability. Here, we show that Ataxia-Telangiectasia Mutated (ATM) is localized to the centrosome and co-purified with gamma-tubulin. The importance of ATM in centrosome duplication is demonstrated in Atm-deficient primary mouse embryonic fibroblasts that display centrosome amplification. Interestingly, centrosome amplification was not observed in tumor cell lines derived from Atm and p21 double deficient mouse. Our results also indicate that both p53 and p21 operate in the same pathway as ATM in regulating centrosome biogenesis. Finally, a potential role of ATM in spindle checkpoint regulation is demonstrated by which ATM protein is activated by mitotic stress. These results suggest a role of ATM in spindle checkpoint regulation and indicate that ATM suppresses genome instability and cellular transformation by regulating centrosome biogenesis.

Animals↗
PubMed2004

DNA end joining becomes less efficient and more error-prone during cellular senescence.

Accumulation of somatic mutations is thought to contribute to the aging process. Genomic instability has been shown to increase during aging, suggesting an aberrant function of DNA double-strand break (DSB) repair. Surprisingly, DSB repair has not been examined with respect to cellular senescence. Therefore, we have studied the ability of young, presenescent, and senescent normal human fibroblasts to repair DSBs in transfected DNA by using a fluorescent reporter substrate. We have found that the efficiency of end joining is reduced up to 4.5 fold in presenescent and senescent cells, relative to young cells. Sequence analysis of end junctions showed that the frequency of precise ligation was higher in young cells, whereas end joining in old cells was associated with extended deletions. These results indicate that end joining becomes inefficient and more error-prone during cellular senescence. Furthermore, the ability to use microhomologies for end joining was compromised in senescent cells, suggesting that young and senescent cells may use different end joining pathways. We hypothesize that inefficient and aberrant end joining is a likely mechanism underlying the age-related genomic instability and higher incidence of cancer in the elderly.

Cellular Senescence↗
PubMed2003

Genes and pathways driving glioblastomas in humans and murine disease models.

Human malignant gliomas arise from neural progenitor cells and/or dedifferentiated astrocytes. By now, they are genetically so well characterized that several murine glioma models have emerged that faithfully reiterate the typical histological features of the disease. In experimental animals, only one or two elements of the growth factor/Ras, PI3K/PTEN/PKB, p53/ARF/HDM2, and p16/Rb/cyclinD/CDK4 pathways are targeted. In human gliomas, many additional genes and pathways are targeted due to a most severe mutator phenotype that leads to the accumulation of countless epigenetic and genetic alterations. Changes that convey a growth advantage are selected for, leading to overgrowth of precursor cell populations with increasingly malignant tumor cell clones. While murine models represent a powerful tool for elucidating the role of genetic pathways, mechanisms of response and resistance to new therapeutic agents might be fundamentally different due to the high degree of genomic instability in the human disease. In fact, little is known about the molecular causes of genomic instability involved in gliomas, except for the rare Turcot's syndrome, O(6)-methylguanine-DNA methyltransferase, and the apurinic/apyrimidinic endonuclease Ape-1. Novel approaches that selectively exploit fundamental metabolic differences between tumor and normal cells have to consider these fundamental differences between human disease and presently available, highly sophisticated animal models.

Animals↗
PubMed2024

The immediate-early protein 1 of human herpesvirus 6B interacts with NBS1 and inhibits ATM signaling.

Viral infection often trigger an ATM serine/threonine kinase (ATM)-dependent DNA damage response in host cells that suppresses viral replication. Viruses evolved different strategies to counteract this antiviral surveillance system. Here, we report that human herpesvirus 6B (HHV-6B) infection causes genomic instability by suppressing ATM signaling in host cells. Expression of immediate-early protein 1 (IE1) phenocopies this phenotype and blocks homology-directed double-strand break repair. Mechanistically, IE1 interacts with NBS1, and inhibits ATM signaling through two distinct domains. HHV-6B seems to efficiently inhibit ATM signaling as further depletion of either NBS1 or ATM do not significantly boost viral replication in infected cells. Interestingly, viral integration of HHV-6B into the host's telomeres is not strictly dependent on NBS1, challenging current models where integration occurs through homology-directed repair. Given that spontaneous IE1 expression has been detected in cells of subjects with inherited chromosomally-integrated form of HHV-6B (iciHHV-6B), a condition associated with several health conditions, our results raise the possibility of a link between genomic instability and the development of iciHHV-6-associated diseases.

Humans↗
PubMedDate not supplied

Altered expression and new mutations in DNA mismatch repair genes MLH1 and MSH2 in melanoma brain metastases.

Brain metastases, including those of malignant melanoma (known for its high genomic instability), are the most common intracranial tumors. The main objective of this study was to investigate expression and mutation in the DNA mismatch repair system in melanoma brain metastases. Expression of MLH1, MSH2, PMS1 and PMS2 was investigated immunohistochemically in 31 melanoma metastatic tumors. Mutational analysis of MLH1 and MSH2 was performed in 17 melanoma brain metastases. Loss of MLH1 and MSH2 expression was found in 10/31 and 12/31 tumors. PMS1 (27/31) and PMS2 (28/31) expression was preserved in the majority of lesions. Potential missense mutation was found in MSH2 (exon 13) in 2/17 melanomas. Mutation in the intron sequence between exon 14 and 15 of MLH1 (exon 15) was observed in 4/17 cases. Our results indicate that the two major DNA mismatch repair genes, MLH1 and MSH2, are more frequently affected by alterations in the DNA mismatch repair system than the helper genes PMS1 and PMS2. The presence of mutations of MSH2 and MLH1 in melanoma brain metastases, which has not been found in primary melanomas, indicates the high genomic instability of melanoma brain metastases.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Rad50 depletion impacts upon ATR-dependent DNA damage responses.

The Mre11/Rad50/NBS1 (MRN) complex is mutated in inherited genomic instability syndromes featuring cancer predisposition, mental retardation and immunodeficiency. It functions both in DNA double-strand break repair and in controlling the ataxia telangiectasia mutated (ATM) kinase during the response to these lesions. Patients inheriting homozygosity for an NBS1 hypomorphic allele display reduced phosphorylation of signaling factors such as Chk1, but not of chromatin-associated factor H2AX, after stresses that activate the ATM-related kinase, ATR. Therefore, we tested whether MRN has a global controlling role over the ATR kinase through the study of MRN deficiencies generated via RNA interference. We show for the first time that MRN is required for ATR-dependent phosphorylation of structural maintenance of chromosomes 1 (Smc1), which acts within chromatin to ensure sister chromatid cohesion and to effect several DNA damage responses. We have uncovered novel phenotypes caused by MRN deficiency that support a functional link between this complex, ATR and Smc1, including hypersensitivity to UV exposure, a defective UV responsive intra-S phase checkpoint and a specific pattern of genomic instability. In addition, certain ATR-dependent responses do not require MRN. These studies demonstrate that there is indeed a controlling role for MRN over the ATR kinase and have established that the downstream events under this control are broad, including both chromatin-associated and diffuse signaling factors, but may not be universal. These studies contribute to our understanding of the central role that MRN plays in damage detection and signaling, which serve to maintain genomic stability and resist neoplastic transformation.

Acid Anhydride Hydrolases↗
PubMed2006

Telomeric aggregates and end-to-end chromosomal fusions require myc box II.

Telomeres of tumor cells form telomeric aggregates (TAs) within the three-dimensional (3D) interphase nucleus. Some of these TAs represent end-to-end chromosomal fusions and may subsequently initiate breakage-bridge-fusion cycles. Wild-type (wt) and myc box II mutant (mt) Myc induce different types of genomic instability when conditionally expressed in mouse proB cells (Ba/F3). Only wt Myc overexpressing Ba/F3 cells are capable of tumor formation in severe combined immunodeficient mice. In this study, we investigated whether telomere dysfunction leading to TA formation is linked to the genetic changes that permit wt c-Myc-dependent transformation of Ba/F3 cells. To this end, we examined the 3D organization of telomeres after the deregulated expression of deletion myc boxII mutant (Delta106) or wt Myc. Delta106-Myc overexpression did not induce TAs, whereas wt-Myc deregulation did. Instead, Delta106-Myc remodelled the 3D telomeric organization such that telomeres aligned in the center of the 3D interphase nucleus forming a telomeric disk owing to a Delta106-induced G1/S cell cycle arrest. In contrast, wt-Myc overexpression led to distorted telomere distribution and TA formation. Analysis of chromosomal alterations using spectral karyotyping confirmed Delta106-Myc and wt-Myc-associated genomic instability. A significant number of chromosomal end-to-end fusions indicative of telomere dysfunction were noted in wt-Myc-expressing cells only. This study suggests that TAs may play a fundamental role in Myc-induced tumorigenesis and provides a novel way to dissect tumor initiation.

Animals↗
PubMed1994

Carcinogenesis, genetic instability and genomic entropy: insight derived from malignant brain tumor age specific mortality rate dynamics.

Aging-related carcinogenesis has been attributed to inherent genetic instability, which manifests in a multistep fashion by activation of oncogenes and inactivation of tumor suppressor genes. Malignant brain tumor cells display multiple-characteristic acquired genetic abnormalities in oncogenes and tumor suppressor genes. Age-specific malignant brain tumor mortality rates in the United States from 1962 to 1988 were interpreted by longitudinal Gompertzian analysis. Utilizing a thermodynamic perspective of the Strehler-Mildvan modification of the Gompertz relationship between mortality and aging, a measure of the rate of increase in informational entropy for those genetic factors involved in the carcinogenesis of malignant brain tumor was determined. Aging-related carcinogenesis can be viewed as a natural consequence of increasing informational entropy of the genome.

Adult↗
PubMed1999

Previous loss of chromosome 11 containing a suppressor locus increases radiosensitivity, neoplastic transformation frequency and delayed death in HeLa x fibroblast human hybrid cells.

CGL1 (HeLa x fibroblast) hybrid cells have been utilized to study mechanisms of radiation-induced neoplastic transformation of human cells in vitro. Previous analysis has shown that loss of active tumor suppressor alleles on fibroblast chromosomes 11 and 14 may be required for radiation-induced neoplastic transformation of CGL1 cells. Loss of chromosome 11 alone was, therefore, found to be necessary but not sufficient for neoplastic transformation. We postulated that the loss of chromosome 11 may make the hybrid cells more susceptible to radiation-induced neoplastic transformation, since these cells have already undergone one of the required tumor suppressor loss events. Hybrid cells which have lost one copy of chromosome 11 were designated CON104(-11). CON104(-11) hybrid cells were found to have increased X-ray sensitivity and susceptibility to radiation-induced neoplastic transformation when compared with the parental CGL1 cells. In addition, the neoplastically transformed foci appear to arise earlier after radiation exposure in CON104(-11) versus CGL1 cells. Furthermore, the plating efficiency (PE) of the progeny of the irradiated CON104(-11) cells, growing in transformation flasks, is persistently lower than parental CGL1 cells during the 21 day assay period. The lower PE of the progeny of irradiated cells was attributed to the expression of delayed death/lethal mutations post-irradiation, a reflection of genomic instability. Taken together, the data indicate that previous loss of chromosome 11 may increase the radiation-induced genomic instability of the hybrid cells, leading to increased radiation sensitivity and neoplastic transformation potential. The data suggest that one possible function of the chromosome 11 tumor suppressor gene may be to help maintain genome stability after radiation damage.

Cell Death↗
PubMed2001

DNA instability and human disease.

It is now well established that non-Mendelian examples of DNA instability are associated with human disease. Most malignancies are associated with various chromosomal instabilities, such as aneuploidy, gene amplification, and chromosomal deletion. Furthermore, widespread microsatellite instability (MSI) is associated with a variety of tumors, and instability at specific dynamic repeat expansions underlies a family of neurologic disorders. Inactivation of DNA mismatch repair genes results in genomic instabilities affecting microsatellite regions. Mutations in genes involved in DNA polymerization or Okazaki fragment processing are also associated with MSI. Such instabilities convey a 'mutator' phenotype which is pathogenic. The mechanisms controlling trinucleotide repeat expansions are less well understood. Why this type of genomic instability is particularly pathogenic to neurons is also not clear. An understanding of what normally maintains stability is the first step towards preventing such loss of control and maintaining health.

Cell Transformation, Neoplastic↗
PubMed2002

Characterization of the slow-growth phenotype of S. cerevisiae Whip/Mgs1 Sgs1 double deletion mutants.

RecQ DNA helicases from many organisms have been indicated to function in the maintenance of genomic stability. In human cells, mutation in the WRN helicase, a RecQ-like DNA helicase, results in the Werner syndrome (WS), a genetic disorder characterized by genomic instability and premature ageing. Similarly, mutation in SGS1, the RECQ homologue in budding yeast, results in genomic instability and accelerated ageing. We previously demonstrated that mouse WRN interacts physically with a novel, highly conserved protein that we named WHIP, and that in budding yeast cells, simultaneous deletion of WHIP/MGS1 and SGS1 results in slow growth and shortened life span. Here we show by using genetic analysis in Saccharomyces cerevisiae that mgs1Delta sgs1Delta cells have increased rates of terminal G2/M arrest, and show elevated rates of spontaneous sister chromatid recombination (SCR) and rDNA array recombination. Finally, we report that complementation of the synthetic relationship between SGS1 and WHIP/MGS1 requires both the helicase and Top3-binding activities of Sgs1, as well as the ATPase activity of Mgs1. Our results suggest that Whip/Mgs1 is implicated in DNA metabolism, and is required for normal growth and cell cycle progression in the absence of Sgs1.

Adenosine Triphosphatases↗
PubMed2026

A high-quality draft genome assembly of Johnsongrass illuminates relationships between polyploidization, crop-wild hybridization, and reproductive biology.

Johnsongrass [Sorghum halepense (L.) Pers.] is an allopolyploid, rhizomatous, perennial grass species and one of the most troublesome weeds in global agriculture. We assembled the first Johnsongrass genome to clarify poorly understood genetic factors influencing variable rates of crop-wild hybridization with cultivated sorghum [S. bicolor (L.) Moench]. The draft genome assembly has a total size of 3.26 Gb and BUSCO completeness of 95.3%. We also report the first evolutionary analysis of INHIBITION OF ALIEN POLLEN (IAP), the only known cross-(in)compatibility locus in the genus. Our results reveal an evolutionary history of genome instability, including the loss of distinct parental subgenomes, and suggest that Nebraska accession 'J-37,' the genome donor, is a segmental allotetraploid that may function as a diploid or aneuploid during meiosis. Genome instability could explain observations of variable ploidies in Johnsongrass and facilitate ongoing hybridization with sorghum where gamete ploidies and IAP alleles match. Given this information, we provide a suggested research framework for studying evolution and gene expression in the Sorghum genus where crop-wild hybridization occurs and for predicting the potential for hybridization between specific crossing partners. Collectively, this work will bolster efforts to study and manage reproductive biology in other crop-wild polyploid complexes.

Sorghum↗
PubMed2006

Adaptive stress response in segmental progeria resembles long-lived dwarfism and calorie restriction in mice.

How congenital defects causing genome instability can result in the pleiotropic symptoms reminiscent of aging but in a segmental and accelerated fashion remains largely unknown. Most segmental progerias are associated with accelerated fibroblast senescence, suggesting that cellular senescence is a likely contributing mechanism. Contrary to expectations, neither accelerated senescence nor acute oxidative stress hypersensitivity was detected in primary fibroblast or erythroblast cultures from multiple progeroid mouse models for defects in the nucleotide excision DNA repair pathway, which share premature aging features including postnatal growth retardation, cerebellar ataxia, and death before weaning. Instead, we report a prominent phenotypic overlap with long-lived dwarfism and calorie restriction during postnatal development (2 wk of age), including reduced size, reduced body temperature, hypoglycemia, and perturbation of the growth hormone/insulin-like growth factor 1 neuroendocrine axis. These symptoms were also present at 2 wk of age in a novel progeroid nucleotide excision repair-deficient mouse model (XPD(G602D/R722W)/XPA(-/-)) that survived weaning with high penetrance. However, despite persistent cachectic dwarfism, blood glucose and serum insulin-like growth factor 1 levels returned to normal by 10 wk, with hypoglycemia reappearing near premature death at 5 mo of age. These data strongly suggest changes in energy metabolism as part of an adaptive response during the stressful period of postnatal growth. Interestingly, a similar perturbation of the postnatal growth axis was not detected in another progeroid mouse model, the double-strand DNA break repair deficient Ku80(-/-) mouse. Specific (but not all) types of genome instability may thus engage a conserved response to stress that evolved to cope with environmental pressures such as food shortage.

Aging↗
PubMedDate not supplied

DNA amplification by breakage/fusion/bridge cycles initiated by spontaneous telomere loss in a human cancer cell line.

The development of genomic instability is an important step in generating the multiple genetic changes required for cancer. One consequence of genomic instability is the overexpression of oncogenes due to gene amplification. One mechanism for gene amplification is the breakage/fusion/bridge (B/F/B) cycle that involves the repeated fusion and breakage of chromosomes following the loss of a telomere. B/F/B cycles have been associated with low-copy gene amplification in human cancer cells, and have been proposed to be an initiating event in high-copy gene amplification. We have found that spontaneous telomere loss on a marker chromosome 16 in a human tumor cell line results in sister chromatid fusion and prolonged periods of chromosome instability. The high rate of anaphase bridges involving chromosome 16 demonstrates that this instability results from B/F/B cycles. The amplification of subtelomeric DNA on the marker chromosome provides conclusive evidence that B/F/B cycles initiated by spontaneous telomere loss are a mechanism for gene amplification in human cancer cells.

Anaphase↗
PubMed1994

The yeast type I topoisomerase Top3 interacts with Sgs1, a DNA helicase homolog: a potential eukaryotic reverse gyrase.

We have previously shown that cells mutant for TOP3, a gene encoding a prokaryotic-like type I topoisomerase in Saccharomyces cerevisiae, display a pleiotropic phenotype including slow growth and genome instability. We identified a mutation, sgs1 (slow growth suppressor), that suppresses both the growth defect and the increased genomic instability of top3 mutants. Here we report the independent isolation of the SGS1 gene in a screen for proteins that interact with Top3. DNA sequence analysis reveals that the putative Sgs1 protein is highly homologous to the helicase encoded by the Escherichia coli recQ gene. These results imply that Sgs1 creates a deleterious topological substrate that Top3 preferentially resolves. The interaction of the Sgs1 helicase homolog and the Top3 topoisomerase is reminiscent of the recently described structure of reverse gyrase from Sulfolobus acidocaldarius, in which a type I DNA topoisomerase and a helicase-like domain are fused in a single polypeptide.

Amino Acid Sequence↗