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At least 1,099 records · Page 61Linked to original sources
PubMed2006

Long inverted repeats in eukaryotic genomes: recombinogenic motifs determine genomic plasticity.

Inverted repeats are unstable motifs in a genome, having a causal relation to fragment rearrangements and recombination events. We have investigated long inverted repeats (LIR) of > 30 bp in length in eukaryotic genomes to assess their contribution to genome stability. An algorithm was first designed for searching for LIRs with < 2 kb internal spacers and >85% identity (degree of homology between repeat copies of a LIR). There are much fewer LIRs in yeast, fruitfly, pufferfish and chicken than in Caenorhabditis elegans, zebrafish, frog and human. However, the high LIR frequencies do not necessarily imply high genome instability because of variant internal spacers and stem lengths and identities. From the collection of identified LIRs, we selected recombinogenic LIRs that had a short internal spacer and a high copy identity and were prone to induce high instability. We found that a relatively high proportion (5-9.8%) of the LIRs in C. elegans, zebrafish and frog were recombinogenic LIRs. In contrast, the proportions in human and mouse LIRs were quite low (0.4-1.1%) basically accounting for long internal spacers. We suggest that C. elegans, zebrafish and frog genomes are unstable in terms of the LIR frequency and the proportion of recombinogenic LIRs. For the other genomes, LIRs most likely have a minor impact.

Algorithms↗
PubMed2003

A genome-wide screen identifies 27 genes involved in transposon silencing in C. elegans.

Transposon jumps are a major cause of genome instability. In the C. elegans strain Bristol N2, transposons are active in somatic cells, but they are silenced in the germline, presumably to protect the germline from mutations. Interestingly, the transposon-silencing mechanism shares factors with the RNAi machinery. To better understand the mechanism of transposon silencing, we performed a genome-wide RNAi screen for genes that, when silenced, cause transposition of Tc1 in the C. elegans germline. We identified 27 such genes, among which are mut-16, a mutator that was previously found but not identified at the molecular level, ppw-2, a member of the argonaute family, and several factors that indicate a role for chromatin structure in the regulation of transposition. Some of the newly identified genes are also required for cosuppression and therefore represent the shared components of the two pathways. Since most of the newly identified genes have clear homologs in other species, and since transposons are found from protozoa to human, it seems likely that they also protect other genomes against transposon activity in the germline.

Animals↗
PubMed2003

Rearrangements of ribosomal DNA clusters in late generation telomerase-deficient Arabidopsis.

The ends of eukaryotic chromosomes are capped with special nucleoprotein structures called telomeres. Telomere shortening due to telomerase inactivation may result in fusion of homologous or heterologous chromosomes, leading to their successive breakage during anaphase movement, followed by fusion of broken ends in the next cell cycle, i.e. the breakage-fusion-bridge (BFB) cycle. Using fluorescence in situ hybridization (FISH) with 25S rDNA and specific bacterial artificial chromosome (BAC) probes we demonstrate participation of chromosomes 2 and 4 of Arabidopsis thaliana AtTERT null plants in the formation of anaphase bridges. Both homologous and non-homologous chromosomes formed transient anaphase bridges whose breakage and unequal separation led to genome rearrangement, including non-reciprocal translocations and aneuploidy. The 45S rDNA regions located at the ends of chromosomes 2 and 4 were observed in chromosome bridges at a frequency approximately ten times higher than expected in the case of random fusion events. This outcome could result from a functional association of rDNA repeats at nucleoli. We also describe increased variation in the number of nucleoli in some interphase cells with supernumerary rDNA FISH signals. These data indicate that dysfunctional telomeres in Arabidopsis lead to massive genome instability, which is induced by multiple rounds of the BFB mechanism.

Anaphase↗
PubMed2004

p53 protein overexpression and p53 mutation analysis in patients with intestinal metaplasia of the cardia and Barrett's esophagus.

p53 mutation is a common genetic change in human cancers, but the clinical significance is controversial. We studied 68 patients and estimate the prevalence of intestinal metaplasia of cardia (IMC), Barrett's esophagus (BE), and p53 protein overexpression, and described molecular alterations of p53 gene exons 5 to 8. Immunohistochemical analysis showed positive p53 in 56.1-39.1% (IMC) and 60.9% (BE). Molecular analysis showed 36.6% altered cases in exon 5 and 9.8% in exon 7. In conclusion, p53 protein overexpression is common in IMC and BE. The molecular alterations observed may be due to LOH, genomic instability or other unknown alteration.

Adult↗
PubMed2006

Interferon regulatory factor-8 is indispensable for the expression of promyelocytic leukemia and the formation of nuclear bodies in myeloid cells.

Interferon (IFN) regulatory factor-8 (IRF-8), previously known as ICSBP, is a myeloid cell essential transcription factor. Mice with null mutation in IRF-8 are defective in the ability of myeloid progenitor cells to mature toward macrophage lineage. Accordingly, these mice develop chronic myelogenous leukemia (CML). We demonstrate here that IRF-8 is an obligatory regulator of the promyelocytic leukemia (PML) gene in activated macrophages, leading to the expression of the PML-I isoform. This regulation is most effective together with two other transcription factors, IRF-1 and PU.1. PML is a tumor suppressor gene that serves as a scaffold protein for nuclear bodies. IRF-8 is not only essential for the IFN-gamma-induced expression of PML in activated macrophages but also for the formation of nuclear bodies. Reduced IRF-8 transcript levels were reported in CML patients, and a recovery to normal levels was observed in patients in remission following treatment with IFN-alpha. We demonstrate a significant correlation between the levels of IRF-8 and PML in these CML patients. Together, our results indicate that some of the myeloleukemia suppressor activities of IRF-8 are mediated through the regulation of PML. When IRF-8 levels are compromised, the reduced PML expression may lead to genome instability and eventually to the leukemic phenotype.

Animals↗
PubMed2003

The genomic damage estimated by arbitrarily primed PCR DNA fingerprinting is useful for the prognosis of gastric cancer.

BACKGROUND & AIMS: Genomic instability and the accompanying alteration of cancer genes play a major role in tumorigenesis. We evaluated the prognostic significance in gastric cancer of the degree of accumulation of relative genomic damage, assessed by arbitrarily primed polymerase chain reaction DNA fingerprinting. METHODS: Genomic damage was assessed by comparative analysis of paired normal and tumor tissue DNA fingerprints. The total number of alterations, scored as decreases and increases of band intensity with 2 arbitrary primers, were used as an estimation of the genomic damage fraction in 74 primary gastric cancers. Increases in DNA copy number were also analyzed by array comparative genomic hybridization in a subset of 30 cases. RESULTS: The number of altered bands varied among the tumors from none or a few to more than one third of the approximately 40 fingerprint bands. The relative values of genomic damage were consistent with the quantitative chromosomal alterations observed by array comparative genomic hybridization. When the tumors were stratified into 2 groups-above or below the cutoff of 0.22 for average genomic damage fraction-genomic damage fraction was a valuable prognostic indicator regardless of microsatellite instability status. Multivariate Cox analysis showed that the genomic damage fraction was a prognostic indicator, as well as a stage indicator (P = 0.0189). Survival was significantly diminished in tumors with a genomic damage fraction >0.22 (P = 0.0009). Moreover, in the 46 curative cases, genomic damage fraction was the only independent factor for predicting survival (P = 0.0061). CONCLUSIONS: Our results indicate that the degree of genomic damage estimated by arbitrarily primed polymerase chain reaction fingerprinting is a useful prognostic indicator for gastric cancer.

Adult↗
PubMed2005

Mechanisms of therapy-related carcinogenesis.

Therapy-related cancers, defined as second primary cancers that arise as a consequence of chemotherapy and/or radiotherapy, are unusual in that they have a well-defined aetiology. Knowledge of the specific nature of the initiating exposure and exactly when it occurred has made it easier to identify crucial genetic events and to model these in vitro and in vivo. As such, the study of therapy-related cancers has led to the elucidation of discrete mechanisms of carcinogenesis, including DNA double-strand-break-induced gene translocation and genomic instability conferred by loss of DNA repair. Unsurprisingly, some of these mechanisms seem to operate in the development of sporadic cancers.

Adult↗
PubMed2003

Functions of Saccharomyces cerevisiae 14-3-3 proteins in response to DNA damage and to DNA replication stress.

Two members of the 14-3-3 protein family, involved in key biological processes in different eukaryotes, are encoded by the functionally redundant Saccharomyces cerevisiae BMH1 and BMH2 genes. We produced and characterized 12 independent bmh1 mutant alleles, whose presence in the cell as the sole 14-3-3 source causes hypersensitivity to genotoxic agents, indicating that Bmh proteins are required for proper response to DNA damage. In particular, the bmh1-103 and bmh1-266 mutant alleles cause defects in G1/S and G2/M DNA damage checkpoints, whereas only the G2/M checkpoint is altered by the bmh1-169 and bmh1-221 alleles. Impaired checkpoint responses correlate with the inability to maintain phosphorylated forms of Rad53 and/or Chk1, suggesting that Bmh proteins might regulate phosphorylation/dephosphorylation of these checkpoint kinases. Moreover, several bmh1 bmh2Delta mutants are defective in resuming DNA replication after transient deoxynucleotide depletion, and all display synthetic effects when also carrying mutations affecting the polalpha-primase and RPA DNA replication complexes, suggesting a role for Bmh proteins in DNA replication stress response. Finally, the bmh1-169 bmh2Delta and bmh1-170 bmh2Delta mutants show increased rates of spontaneous gross chromosomal rearrangements, indicating that Bmh proteins are required to suppress genome instability.

14-3-3 Proteins↗
PubMed2006

Mutagenicity of non-homologous end joining DNA repair in a resistant subset of human chronic lymphocytic leukaemia B cells.

Non-homologous end joining (NHEJ) is an important determinant of genomic stability in mammalian cells. This DNA repair pathway is upregulated in a subset of B-cell chronic lymphocytic leukaemia (B-CLL) cells resistant to DNA damage-induced apoptosis. Using an in vitro assay for double-strand breaks (DSB) end ligation, we studied the fidelity of DSB repair in B-CLL cells which were resistant or sensitive to in vitro DSB-induced apoptosis with concomitant patients' resistance or sensitivity to chemotherapy, respectively. The fidelity of DNA repair was determined by DNA sequencing of polymerase chain reaction products cloned in pGEM-T vector. Sequence analysis of DNA end junctions showed that the frequency of accurate ligation was higher in sensitive B-CLL cells and control cell lines, than in resistant cells where end joining was associated with extended deletions. Upregulated and error-prone NHEJ in resistant cells could be a quite possible mechanism underlying both genomic instability and poor clinical outcome.

Aged↗
PubMed2005

Lack of consensus gene expression changes associated with radiation-induced chromosomal instability.

The relatively high frequency with which ionizing radiation induces genomic instability suggests that a gene mutation occurring after irradiation is an unlikely cause of the phenotype. To search for mechanism(s) of initiation and perpetuation of this instability phenotype, gene expression profiles of clones exhibiting delayed chromosomal instability were analyzed. Microarray analysis using two pools of isogenic radiation-induced chromosomally unstable clones compared to an irradiated but chromosomally stable clone uncovered a set of 68 differentially expressed genes using two methods of analysis. Unexpectedly, all 68 genes were under-expressed relative to the chromosomally stable reference clone. Further analysis of the candidates placed the differentially expressed genes into pathways implicating differential MAP kinase signaling, ubiquitin/proteasome function, DNA repair, cell cycle control, lipid signaling, nucleotide metabolism, and other potentially disrupted pathways. Validation studies using northern and western blotting, and functional assays concluded that although differences in some of these pathways exist, no single gene or molecular pathway was found to be differentially regulated in all of the chromosomally unstable clones tested. Inferred from these data is that there are multiple potential molecular pathways and/or events that maintain the unstable phenotype, and no single expression pattern is linked to instability in the unstable clones analyzed.

Animals↗
PubMed1995

Microsatellite instability in squamous cell carcinoma of the head and neck.

Genomic instability or microsatellite instability (MI) in simple repeated sequences was initially recognised in colonic carcinomas and subsequently in other tumours. MI has been associated with mutations in genes concerned with replication and DNA repair. We investigated 34 microsatellite markers in squamous cell carcinoma of the head and neck (SCCHN). Fifty-six tumours, were studied, of which 25 were investigated with ten or more microsatellite markers. In this study we consider two or more microsatellite alterations in a tumour to be diagnostic of MI. We demonstrated that 7/25 (28%) of the tumours had MI at two or more loci and three of these tumours exhibited evidence of 20 or more loci with MI. No correlations were found between MI and previous treatment, site, histological differentiation, positive nodes at pathology, a history of alcohol intake or survival. MI has been demonstrated in T1N0 stage tumours, indicating that these changes may occur early in the disease process. A negative correlation was found between MI and a history of smoking (P = 0.02). Two or more markers of MI were found in three of four non-smokers compared with one of 13 in the smoking group of patients, which suggests a novel mechanism of carcinogenesis in non-smokers.

Carcinoma, Squamous Cell↗
PubMed2005

The accumulation of specific amplifications characterizes two different genomic pathways of evolution of familial breast tumors.

PURPOSE AND METHODS: High-level DNA amplifications are recurrently found in breast cancer, and some of them are associated with poor patient prognosis. To determine their frequency and co-occurrence in familial breast cancer, we have analyzed 80 tumors previously characterized for BRCA1 and BRCA2 germ-line mutations (26 BRCA1, 18 BRCA2, and 36 non-BRCA1/2) using high-resolution comparative genomic hybridization. RESULTS: Twenty-one regions were identified as recurrently amplified, such as 8q21-23 (26.25%), 17q22-25 (13.75%), 13q21-31 (12.50%), and 8q24 (11.25%), many of which were altered in each familial breast cancer group. These amplifications defined an amplifier phenotype that is correlated with a higher genomic instability. Based on these amplifications, two different genomic pathways have been established in association with 8q21-23 and/or 17q22-25 and with 13q21-31 amplification. These pathways are associated with specific genomic regions of amplification, carry specific immunohistochemical characteristics coincident with high and low aggressiveness, and have a trend to be associated with BRCA1 and BRCA2/X, respectively. CONCLUSION: In summary, our data suggest the existence of two different patterns of evolution, probably common to familial and sporadic breast tumors.

Breast Neoplasms↗
PubMed1999

[Molecular mechanism of hepatocarcinogenesis].

Hepatocellular carcinoma (HCC) in Japan is closely associated with the chronic liver diseases of infection with the hepatitis B or C viruses. Analysis of HCC tissues frequently detects loss of heterozygosity at chromosomes 1p, 4, 6q, 8p, 10q, 13q, 16q, 17p, and many genomic and epigenomic abnormalities have been found in p53, beta-catenin, p16CDKI, DNA mismatch repair genes, and others. However, no specific abnormal genetic or epigenetic changes for HCC have been found so far. The development of HCC has been reported in mice transgenic for the hepatitis B virus X gene or the hepatitis C virus core gene, and these viral proteins might play essential roles in hepatocarcinogenesis. Chronic hepatitis and fibrosis due to persistent viral infection might also influence the genomic instability of hepatocytes, leading to accumulation of genomic changes.

Animals↗
PubMedDate not supplied

Analysis of microsatellite instability in acquired drug-resistance human tumor cell lines.

Genomic instability characterized as microsatellite instability (MIN) is associated with loss of DNA mismatch repair (MMR) protein. Several studies have shown that loss of DNA MMR protein confers resistance to some interacting DNA chemotherapeutic drugs, but also that exposure of MMR-proficient cells to these drugs can result in loss of MMR protein accompanied by induction of MIN. Such associations were mainly reported for cisplatin, but scarce data are available for doxorubicin (a DNA interacting agent), and nothing is known about vinblastine (an antitubulin agent). Thus, in this study we have analyzed MIN frequency in different type of human tumor cell lines characterized by their MMR protein status and resistant to doxorubicin or to vinblastine. Relationship between MIN occurrence and drug resistance was firstly verified in cisplatin resistant cells, and showed a MIN enrichment (33%) only in the MMR-deficient cells. In order to determine whether treatment of MMR-proficient cells with doxorubicin might lead to induction of MIN, we analyzed two different MMR-proficient cell lines. Variations of MIN frequency were found with either high levels of MIN (66%) or no MIN at all (0%). Effect of vinblastine was analyzed according to the MMR status in two different MMR-proficient and -deficient cells. No major change in MIN frequency was found either in the MMR-proficient (0%) or -deficient (9%) cells. Our results demonstrate that MIN occurs only in tumor cells resistant to cisplatin or doxorubicin, thus supporting earlier findings reporting such associations only with drugs interacting with DNA. Moreover, the data show that MIN does not appear in all tumor cell lines, suggesting that induction of MIN in relation to MMR status is a complex phenomenon which does not only depend on the drug considered (interacting or not with DNA), but also on the tumor cell variant.

Alleles↗
PubMed2004

Methylenetetrahydrofolate reductase C677T polymorphism, folic acid and riboflavin are important determinants of genome stability in cultured human lymphocytes.

We tested the hypothesis that methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, folic acid deficiency and riboflavin deficiency, independently or interactively, are important determinants of genomic stability, cell death, cell proliferation and homocysteine (Hcy) concentration in 9-d human lymphocyte cultures. Lymphocytes of seven wild-type (CC) and seven mutant (TT) homozygotes were cultured under the four possible combinations of deficiency and sufficiency of riboflavin (0 and 500 nmol/L) and folic acid (20 and 100 nmol/L) at a constant L-methionine concentration of 50 micromol/L. Viable cell growth was 25% greater in TT than in CC cells (P<0.05) and 32% greater at 100 nmol/L folic acid than at 20 nmol/L folic acid (P=0.002). The comprehensive cytokinesis-block micronucleus assay was used to measure micronuclei (MNi; a marker for chromosome breakage and loss), nucleoplasmic bridges (NPB; a marker of chromosome rearrangement) and nuclear buds (NBUD, a marker of gene amplification). The MNi levels were 21% higher in TT cells than in CC cells (P<0.05) and 42% lower in the high folic acid medium than in the low folic acid medium (P<0.0001). The NBUD levels were 27% lower in TT cells than in CC cells (P<0.05) and 45% lower in the high folic acid medium than in the low folic acid medium (P<0.0001). High riboflavin concentration (500 nmol/L) increased NBUD levels by 25% (compared with 0 nmol/L riboflavin) in folate-deficient conditions (20 nmol/L folic acid medium; P<0.05), and there was an interaction between folic acid and riboflavin that affected NBUD levels (P=0.042). This preliminary investigation suggests that MTHFR C677T polymorphism and riboflavin affect genome instability; however, the effect is relatively small compared with that of folic acid.

Adult↗
PubMed2006

Dual-color-coded imaging of viable circulating prostate carcinoma cells reveals genetic exchange between tumor cells in vivo, contributing to highly metastatic phenotypes.

Color-coded imaging analysis revealed yellow fluorescent metastasis precursor cells that were readily recognized in the blood of tumor-bearing mice after mixtures of red fluorescent protein (RFP)- and green fluorescent protein (GFP)-expressing PC-3 human prostate carcinoma cells were implanted in the nude mouse prostate and metastasized. The yellow fluorescent cells were purified from the blood of nude mice to 99% homogeneity by FACS, expanded in culture, and reimplanted in the prostate of nude mice. The yellow fluorescent phenotype was heritable and stably maintained by tumor cells for many generations in vitro and in vivo. In the animals implanted with the yellow-fluorescing cells, 100% developed aggressive metastatic cancer. Lung metastases were demonstrated in 100% of the animals as early as four weeks after injection of the yellow-fluorescing cells in the mouse prostate. In contrast, when the GFP- and RFP-expressing parental cells were inoculated into the mouse prostate separately, none of the animals developed lung metastasis. All animals had almost exclusively yellow fluorescent cells in the blood and bone marrow. These results are consistent with the idea that spontaneous genetic exchange between tumor cells in vivo contributes to genomic instability and creation of highly metastatic cells.

Animals↗
PubMed2005

Expression of mismatch repair enzymes, hMLH1 and hMSH2 is not associated with microsatellite instability and P53 protein accumulation in basal cell carcinoma.

Microsatellite instability (MSI) constitutes an alternative-to the chromosomal instability-pathway of carcinogenesis for certain tumour types with prognostic and therapeutic significance for the respective patients. MSI is caused by mutations in mismatch repair (MMR) genes, mainly hMLH1, hMSH2, leading to a defective MMR system. The role of MSI in basal cell carcinoma (BCC) has not been clearly delineated yet. p53 gene as a target for ultraviolet radiation-induced mutations may enhance genomic instability in BCC, with loss of its function. Our aim was to investigate the involvement of MSI and expression of hMLH1 and hMSH2 in parallel with P53 protein accumulation in the pathogenesis of BCC and its possible correlation to the clinicopathological features of the patients. The presence of MSI was investigated in 76 BCCs using mononucleotide microsatellite markers, BAT-25, BAT-26 and TGF-beta receptor type II (TGF-beta-RII). Additionally, 3 dinucleotide markers were analysed in 20 cases in which matched normal tissue was available. The expression of hMLH1, hMSH2 and P53 proteins was evaluated by immunohistochemical analysis. Alterations of the BAT-26 marker were observed in one fibroepithelioma of Pincus, one nodular and one multifocal superficial BCC. A keratotic BCC showed an altered BAT-25 locus. Two samples, a multifocal superficial and a nodular BCC, displayed MSI at two markers (BAT-25 and BAT-26; and BAT-25 and TGF-beta-RII, respectively). Three more cases, a metatypical, a multifocal superficial and a signet ring BCC exhibited frameshift mutations in the TGF-beta-RII. No sample showed length alterations at the dinucleotide markers examined. hMLH1 and hMSH2 protein immunohistochemical expression was scored positive in 46 and 49 out of 52 cases respectively. P53 accumulation was observed in 27 out of 56 samples. Correlation of the molecular and immunohistochemical findings with the clinicopathological parameters produced no statistically significant results. No correlation between MSI and hMLH1, hMSH2 or P53 protein expression was determined. MSI appears to play a minor role in the pathogenesis of BCCs being present only in a small subset of such tumours.

Adaptor Proteins, Signal Transducing↗
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↗