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PubMed1991

Preferential integration of marker DNA into the chromosomal fragile site at 3p14: an approach to cloning fragile sites.

Fragile sites are specific regions of chromosomes that are prone to breakage. In cells cultured under conditions that induce fragile site expression, high levels of inter- and intrachromosomal recombination have been observed involving chromosomal bands containing fragile sites. To determine whether expression of specific fragile sites would facilitate preferential integration of exogenous DNA at these recombination hot spots, the vector pSV2Neo was transfected into a Chinese hamster-human somatic cell hybrid containing a derivative chromosome 3 as its only human component. Chromosome 3 contains a common fragile site at band 3p14.2 (FRA3B) that is induced by aphidicolin. Both cells induced to express FRA3B and the uninduced control cells were transfected with the pSV2Neo selectable plasmid. In situ hybridization of a biotin-labeled pSV2Neo probe to metaphase chromosomes revealed one to three integration sites in each stably transfected clone. Four of 13 clones transfected under conditions of FRA3B induction showed integration of pSV2Neo at 3p14; these clones also showed specific integration into hamster chromosome 1 and a rearranged chromosome characteristic of CHO cells (mar2). The 7 control clones, however, showed an apparently random pattern of pSV2Neo integration. Significant hybridization of pSV2Neo to both FRA3B and Chinese hamster chromosomes 1 and mar2 was seen in 100 cells from pooled colonies transfected after treatment with aphidicolin. These results suggest that preferential integration of marker DNA into human and Chinese hamster fragile sites occurs with exposure to aphidicolin. The nature of the DNA sequences at fragile sites is unknown and, despite a number of approaches, these sequences have not yet been isolated; our procedure may represent an approach to the cloning of fragile sites.

Animals↗
PubMed2002

Expression of folate sensitive and aphidicolin induced chromosomal fragile sites in familial neuroblastoma.

The expression of folate sensitive and aphidicolin induced fragile sites in the blood lymphocyte chromosomes of affected and unaffected members from 2 neuroblastoma families were studied. The subjects included 4 neuroblastoma patients, and 9 of their clinically healthy first degree relatives and corresponding number of age and sex matched controls. Lymphocytes cultured in folate deprived culture medium showed rare fragile sites at band p13.1 of chromosome 1, in a frequency of 3%-5% in all the 4 neuroblastoma patients. In aphidicolin treated cultures, the patients and unaffected members in neuroblastoma families, showed hypersensitivity to aphidicolin, as evidenced by the significant increase in percentage of aberration/cell (ab/c) and damaged cells (dc), over that of controls (P < 0.01). Aphidicolin induced fragile sites were more pronounced in chromosomes 1 and 2. A larger number of subjects have to be studied to prove whether altered fragile site expression may be a cytogenetic evidence for an individual or familial cancer predisposing genetic constitution.

Aphidicolin↗
PubMed1992

[Chromosomal restructurings and the distribution of chromosome fragile sites in the peripheral blood lymphocytes in a breast cancer patient after cytostatic therapy].

Cytogenetic analysis was performed repeatedly on a breast cancer patient since the beginning of the antitumor treatment. Double minute chromosomes (DMS, 2-10 per cell) were found in less than 2% of peripheral blood lymphocytes besides other chromosomal abnormalities after radiation therapy and 8 months after chemotherapy. The level of structural chromosomal aberrations two years after the therapeutic treatment was 0.13-0.14 aberrations per cell, but DMS were not observed. Estimation of the fragile site (FS) frequency and distribution at this time revealed a significant expression of the common FS FRAGF (9q1.2) after the treatment of blood culture with 5-bromo-2-deoxyuridine at dose levels of 7 and 50 g/l and enhanced fragility in chromosome band 1p35-36.1 (FRA1A) in folate-deprived conditions. Rare FS were not found. The presented data are discussed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1984

Chromosome fragility in patients with sporadic unilateral retinoblastoma.

Banded karyotypes were prepared from short-term cultures of lymphocytes from the peripheral blood of ten patients with untreated sporadic unilateral retinoblastoma and ten matched controls. Different types of structural chromosome aberrations were observed in the patients, including a statistically significant increase of chromatid and isochromatid gaps and breaks.

Adolescent↗
PubMedDate not supplied

Enhanced chromosomal fragility in neuroblastoma: correlation with poor prognosis.

In a previous study we demonstrated spontaneous fragility and hypersensitivity to fragile site induction by aphidicolin in lymphocytes from some neuroblastoma patients and their parents. Here we report data based on a total of 40 patients and 37 families. Possible correlations between higher sensitivity to aphidicolin and a variety of personal and clinical characteristics were verified. Patients with a poor prognosis generally proved to be more susceptible to fragile site induction.

Adult↗
PubMed1981

Chromosome fragility in New Zealand black mice: effect of syngeneic, allogeneic, and xenogeneic sera on fetal fibroblasts in vitro.

The sensitivity of fetal fibroblasts from New Zealand Black (NZB) and BALB/c mice to syngeneic, allogenic, and xenogeneic sera was tested. The NZB fetal fibroblasts manifested significantly more chromosome abnormalities when grown in the presence of syngeneic sera or in one of three tested allogeneic sera but no in xenogeneic sera. In contrast, no chromosome fragility was observed in BALB/c fetal fibroblasts tested under similar conditions. These findings suggested that NZB fetal fibroblasts are not generally unstable but that the instability is expressed only in response to specific factors(s) present in syngeneic sera from young and old mice.

Age Factors↗
PubMed2006

WWOX, a chromosomal fragile site gene and its role in cancer.

Allelic imbalances affecting the long arm of chromosome 16 have been extensively reported in the literature as common abnormalities observed in various carcinoma types, As a result of loss of heterozygosity (LOH) studies in breast cancer, we delimited a genomic area within chromosome 16 that demonstrated the highest frequency of abnormalities. This led us to the identification and cloning of WWOX, a candidate tumor suppressor gene (TSG) that spans a fragile region of DNA located at 16q23.3-24.1 (FRA16D: the second most active common chromosomal fragile site in the human genome). This gene encodes a protein that contains two WW domains responsible of protein-protein interactions and a short-chain dehydrogenase (SDR) domain likely involved in sex steroid metabolism. Protein-protein interactions of WWOX with other peptides that act as apoptotic regulators as well as nuclear transcription factors have been described. We and other groups have studied the expression of WWOX in multiple tumor types in hormonally and nonhormonally regulated organs. In these studies, a significant correlation of loss of WWOX protein expression, with sex steroid hormone receptors expression and patient outcome, has been demonstrated. Reinsertion of the WWOX gene in WWOX-deficient tumorigenic cancer cell lines has shown a dramatic decrease of tumor growth in vivo, while inhibition of anchorage independent growth was observed in vitro. Further studies are necessary to elucidate the exact biological role of WWOX as a suppressor of tumor growth.

Breast Neoplasms↗
PubMed1994

Chromosome fragility and instability in human cancer.

The development of cancer is a multistep process triggered by physical, chemical, or biological carcinogenic factors, with the progression to an invasive phenotype requiring cumulative genetic alterations. Not all cellular genomic sequences are equally susceptible to carcinogenic factors or involved in pathologically relevant genetic alterations. Because of structural chromatin organization and DNA replication, certain genomic regions exhibit an increased fragility and tendency to recombination. At these regions, called fragile sites, there is a convergence of specific deletions, translocations, chemically induced lesions, and virus integrations. Isolation and cloning of sequences at fragile sites are important to a better understanding of the carcinogenesis process and to development of preventive measures.

Chromosome Fragile Sites↗
PubMed1993

Bromodeoxyuridine induces chromosomal fragile sites in the canine genome.

Peripheral blood lymphocytes from 3 clinically normal domestic dogs were cultured for bromodeoxyuridine (BrdU) induction of fragile site expression. BrdU induced fragile site expression in cells from all 3 dogs. The mean percent of cells with fragile sites and the mean number of fragile sites per cell were significantly increased in all BrdU incubated cultures compared to control cultures. The frequency of BrdU fragile site expression did not vary significantly among the dogs. Lymphocytes from all 3 dogs expressed BrdU induced autosomal fragile sites. Two BrdU induced fragile sites were identified on the long arm of chromosome 1, one of which was close to or coincident with a previously identified folate sensitive fragile site on this canine chromosome. Lymphocytes from the 2 female dogs also expressed BrdU induced fragile sites on the X chromosome, but BrdU failed to induce fragile sites on the X chromosome from the one male dog in the study. The 2 BrdU-induced fragile sites identified on the long arm of the X chromosome were close to, or coincident with 2 previously described folate-sensitive common fragile sites on the canine X chromosome. This is the first report of induction of BrdU-inducible fragile sites in the genome of the domestic dog.

Animals↗
PubMed1998

A tandem array of minimal U1 small nuclear RNA genes is sufficient to generate a new adenovirus type 12-inducible chromosome fragile site.

Infection of human cells with adenovirus serotype 12 (Ad12) induces metaphase fragility of four, and apparently only four, chromosomal loci. Surprisingly, each of these four loci corresponds to a cluster of genes encoding a small abundant structural RNA: the RNU1 and RNU2 loci contain tandemly repeated genes encoding U1 and U2 small nuclear RNAs (snRNAs), respectively; the PSU1 locus is a cluster of degenerate U1 genes; and the RN5S locus contains the tandemly repeated genes encoding 5S rRNA. These observations suggested that high local levels of transcription, in combination with Ad12 early functions, can interfere with metaphase chromatin packing. In support of this hypothesis, we and others found that an artificial tandem array of transcriptionally active, but not inactive, U2 snRNA genes would generate a novel Ad12-inducible fragile site. Although U1 and U2 snRNA are both transcribed by RNA polymerase II and share similar enhancer, promoter, and terminator signals, the human U1 promoter is clearly more complex than that of U2. In addition, the natural U1 tandem repeat unit exceeds 45 kb, whereas the U2 tandem repeat unit is only 6.1 kb. We therefore asked whether an artificial array of minimal U1 genes would also generate a novel Ad12-inducible fragile site. The exogenous U1 genes were marked by an innocuous U72C point mutation within the U1 coding region so that steady-state levels of U1 snRNA derived from the artificial array could be quantified by a simple primer extension assay. We found that the minimal U1 genes were efficiently expressed and were as effective as minimal U2 genes in generating a novel Ad12-inducible fragile site. Thus, despite significant differences in promoter architecture and overall gene organization, the active U1 transcription units suffice to generate a new virally inducible fragile site.

Adenoviruses, Human↗
PubMed2006

Chromosomal fragile site expression in Turkish psychiatric patients.

Chromosomal aberrations associated with psychiatric disorders may suggest regions in which to focus a search for genes predisposing to psychosis by a linkage strategy. Identification of these may be especially important given the unknown pathophysiology and the probable genetic heterogeneity of psychiatric disorders. In this study, the frequencies of folate sensitive fragile sites (FS) were compared among psychiatric disorders (e.g., schizophrenia, bipolar disorder, and other psychosis) and normal individuals. The rate of FS expression in the patients was considerably higher than in the controls. Sites 1p22, 1q21, 1q32, 2q31, 3p14, 3p25, 5q22, 5q31, 6p21, 6q21, 6q25, 7q22, 7q32, 8q22, 10q21, 11q23, 12q24, 13q32, 14q24, 16q22, 17q21, Xp22 and Xq26 were expressed more frequently in the patients. Thirty possible relevant chromosomal sites were identified in schizophrenia: 1q21, 1q32, 2p13, 2q21, 3p14, 3p25, 3q21, 5q22, 5q31, 6p21, 6q25, 6q26, 7q21, 7q22, 7q32, 8q22, 9q21, 10q21, 11q23, 12q24, 13q32, 14q24, 16q22, 17q21, Xp22, Xq22, and Xq26. Possible relevant sites were also identified in bipolar disorder: sites 1p36, 1q21, 1q32, 3p14, 3p25, 5q31, 7q22, 7q32, 11q23, 12q24, 13q32, 14q24, Xp22, and Xq26. Sites in the other psychosis group were: 1p22, 1p32, 1p36, 1q21, 1q32, 2q31, 3p14, 3p25, 5q31, 6p21, 6q21, 6q25, 6q26, 7q22, 7q32, 8q22, 10q21, 11q23, 12q13, 12q24, 13q32, 16q22, 16q24, 17q21 and Xq26. Among patient groups, there were significant differences in bands 1p32, 2p13, 2q21, 2q31, 3p14, 3p25, 5q31, 6q21, 6q26, 7q22, 7q32, 9q21, 11qq23, 12q13, 12q24, 16q24, and Xq22 between schizophrenic and bipolar patients. These regions were more frequently expressed in schizophrenic patients than in bipolar patients. The 1p22, 1p32, and 16q24 regions were significantly more frequently expressed in the other psychosis group than in the bipolar group. These interesting regions, which may harbor important genes for psychosis, have produced strong support for linkage in the majority of genome scan projects.

Adolescent↗
PubMed1989

Familial and individual variation in chromosome fragility.

An extremely high frequency of fra 6q26 (25%) was detected during a routine cytogenetic investigation of a 9-year-old girl. This prompted us to perform an extensive study of fragile site expression in her cells and those of her parents and sister. The very high frequency of fragility at 6q26 which had been discovered initially in the proband was not detected in the first repeat culture under the same experimental conditions. However, in the second repeat culture fragility at 6q26 was clearly present again. In the 4 members of this family fragile site expression was found to vary significantly between repeat samples from the same person. Also, a specific order of individual fragile site expression appeared to be present. This order was the same for the different culture conditions used.

Aphidicolin↗
PubMed1982

[X-linked mental retardation, macro-orchism, and X chromosome fragile site. Presentation of 6 cases in 2 families].

Six males, four adults and two children, with very important mental deficiency and speech disturbances, belonging to two families are presented. The six patients show the clinical peculiarities of the "X-linked mental retardation, macroorchidism, and the Xq27 fragile site", but the chromosomal alteration only was presented in five cases. Patient who did not have the chromosomal defect presented the same IQ than his brothers, but he had a less severe macroorchidism, a better speech and more normal clinical features. One of the patients shows a shorter arm which linkage with the syndrome is discussed.

Adolescent↗
PubMedDate not supplied

Mouse chromosome fragility.

When cultures of fibroblast-like cells from inbred mouse strains RBC/Dn and AEJ/GnRk were exposed to 5-fluorodeoxyuridine (FUdR), non-random strain-specific distributions of chromosome gaps, breaks and exchanges were observed. Throughout the genomes there appeared to be specific sites at which lesions occurred preferentially. Two strain-specific fragile sites were identified in strain RBC/Dn at G-band 15A2, and at G-band 19B in strain AEJ/GnRk. Constitutive fragile sites at G-bands 12A2 and 18A2 were identified in both strains. A strain-specific marker at G-band 9B was found in strain AEJ/GnRk. The fragile sites reported here provide an animal model for the study of chromosome fragility as well as polymorphic markers for linkage studies.

Animals↗
PubMed2005

Chromatin structure of human chromosomal fragile sites.

Cytological appearance of fragile sites as non-staining gaps in metaphase chromosomes suggests an abnormality in chromatin structure. Studies of fragile sites at three levels of chromosome organization: (1) examining the ability of DNA derived from fragile sites to form nucleosomes-the basic structural element of chromosomes, (2) probing the arrangement of nucleosome arrays over fragile sites in fragile site-expressing cell lines, and (3) visualizing fragile sites in higher-order chromatin organization, reveal an unusual chromatin structure associated with fragile sites. This fragile site-associated chromatin structure might play an active role in DNA metabolic processes such as replication, transcription, repair and recombination, which are closely linked to the instability of fragile sites.

Animals↗