Types, stability, and phenotypic consequences of chromosome rearrangements leading to interstitial telomeric sequences.

Rossi, Elena; Floridia, Giovanna; Casali, Massimiliano; Danesino, Cesare; Chiumello, G; Bernardi, F; Magnani, Ivana; Papi, Laura; Mura, Manuela; Zuffardi, Orsetta

doi:10.1136/jmg.30.11.926

Cited by 65 publications

(55 citation statements)

References 28 publications

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“…[31][32][33][34] JT in such cases are, however, also cytogenetically different compared to hematologic malignancies -they preferentially involve other donor chromosome regions and are not trisomic for the jumping region. [31][32][33][34][35] Altogether, the widespread temporally heterogeneous breakpoints of the donor chromosome and the subtelomeric breakpoints on the recipient chromosomes indicate a complex origin of JT: the multiple clones most likely arose more or less simultaneously, followed by clonal selection. In this context, it is noteworthy that a small clone with +3 preceded the unbalanced JT.…”

Section: Discussionmentioning

confidence: 99%

“…A probe (7 × TTAGGG), which hybridizes to human telomeric sequences, was end-labeled with 32 P-␥-ATP using T4 polynucleotide kinase (Gibco, BRL, Gaithersburg, MD, USA), and hybridized with 5 g Hinf1-digested DNA according to Ohyashiki et al 29 …”

Section: Southern Blot Analysismentioning

confidence: 99%

“…The forward primer of each pair was end-labeled with 32 P-␥-ATP using T4 polynucleotide kinase. PCR was performed in 30 l reactions with 1.5 mM MgCl 2 , 200 M of each dNTP in PCR buffer (Perkin Elmer, Branchburg, NJ, USA), 0.13 M reverse primer, 0.065 M each of end-labeled and non-end-labeled forward primer and 1 unit Amplitaq Gold (Perkin Elmer).…”

Section: Microsatellite Instability Analysis (Mi)mentioning

confidence: 99%

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Molecular characterization of jumping translocations reveals spatial and temporal breakpoint heterogeneity

et al. 1998

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Jumping translocations (JT) are characterized by the relocalization of the same part of a donor to several recipient chromosomes. Although JT occasionally are constitutional, most are associated with hematologic malignancies. In such cases, JT usually arise during disease progression and are associated with poor prognosis. Despite its clinical importance, this cytogenetic phenomenon has not been characterized at the molecular level. We have analyzed JT in a juvenile chronic myelomonocytic leukemia that subsequently transformed to an acute myeloid leukemia. Detailed fluorescence in situ hybridization (FISH) analyses showed that the cytogenetically identical donor breakpoint at 3q21 was highly heterogeneous. In fact, more than 10 distinct breakpoints, four of which mapped within YACs, were identified. Analyses of samples during disease progression showed that the breakpoint complexity decreased, indicating clonal selection. Hence, the 3q21 breakpoints displayed a spatial as well as a temporal heterogeneity, revealing that JT are highly unstable, showing great variation in the size of donor segment. The breaks at the recipient chromosomes were mapped within the subtelomeric regions. The general telomere length was not affected and an underlying replication error resulting in microsatellite instability was excluded. We conclude that the emergence of JT is unlikely to cause fusion genes or to affect the expression of genes located in the breakpoint regions. The identification of YACs spanning the breakpoints, ie, YACs 913c7, 937g5, 948c2 and 955g1, may facilitate the isolation of DNA sequences leading to a genetic instability associated with the origin of multiple translocations.

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Section: Discussionmentioning

confidence: 99%

Section: Southern Blot Analysismentioning

confidence: 99%

Section: Microsatellite Instability Analysis (Mi)mentioning

confidence: 99%

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Molecular characterization of jumping translocations reveals spatial and temporal breakpoint heterogeneity

et al. 1998

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“…They are of interest from a physiological point of view because they have been shown to cause genomic rearrangements in humans as a result of homologous recombination (Vanin et al 1983;Henthorn et al 1986;Hobbs et al 1986;Nicholls et al 1987;Rouyer et al 1987;Rudiger et al 1991). Finally, there is mounting evidence that both interstitial and terminal telomeric repeat sequences are hot spots for recombination in several eukaryotic organisms, including S. cerevisiae (Pluta and Zakian 1989), mice Nachman and Churchill 1996), and humans (Brown et al 1990;Park et al 1992;Rossi et al 1993). In Schizosaccharomyces pombe, homologous pairing of chromosomes was shown to be most frequent near centromeres and telomeres (Scherthan et al 1994).…”

Section: Rad51 Protein-selected Sequences Are Similar To Genetically mentioning

confidence: 99%

The preference for GT-rich DNA by the yeast Rad51 protein defines a set of universal pairing sequences

1997

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The Rad51 protein of Saccharomyces cerevisiae is a eukaryotic homolog of the RecA protein, the prototypic DNA strand-exchange protein of Escherichia coli. RAD51 gene function is required for efficient genetic recombination and for DNA double-strand break repair. Recently, we demonstrated that RecA protein has a preferential affinity for GT-rich DNA sequences-several of which exhibit enhanced RecA protein-promoted homologous pairing activity. The fundamental similarity between the RecA and Rad51 proteins suggests that Rad51 might display an analogous bias. Using in vitro selection, here we show that the yeast Rad51 protein shares the same preference for GT-rich sequences as its prokaryotic counterpart. This bias is also manifest as an increased ability of Rad51 protein to promote the invasion of supercoiled DNA by homologous GT-rich single-stranded DNA, an activity not previously described for the eukaryotic pairing protein. We propose that the preferred utilization of GT-rich sequences is a conserved feature among all homologs of RecA protein, and that GT-rich regions are loci for increased genetic exchange in both prokaryotes and eukaryotes.

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“…It is thought that these interstitial telomere repeats arose as the result of chromosome rearrangements in the course of genome evolution (34,67), a view supported by occasional observation of aberrant chromosomes that have telomere repeats at the site of rearrangement (58). Like repeats at telomeres, interstitial repeats also appear to influence aspects of DNA metabolism in their vicinity.…”

mentioning

confidence: 94%

Insertion of a Telomere Repeat Sequence into a Mammalian Gene Causes Chromosome Instability

Kilburn

Shea

Sargent³

et al. 2001

Molecular and Cellular Biology

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Telomere repeat sequences cap the ends of eucaryotic chromosomes and help stabilize them. At interstitial sites, however, they may destabilize chromosomes, as suggested by cytogenetic studies in mammalian cells that correlate interstitial telomere sequence with sites of spontaneous and radiation-induced chromosome rearrangements. In no instance is the length, purity, or orientation of the telomere repeats at these potentially destabilizing interstitial sites known. To determine the effects of a defined interstitial telomere sequence on chromosome instability, as well as other aspects of DNA metabolism, we deposited 800 bp of the functional vertebrate telomere repeat, TTAGGG, in two orientations in the second intron of the adenosine phosphoribosyltransferase (APRT) gene in Chinese hamster ovary cells. In one orientation, the deposited telomere sequence did not interfere with expression of the APRT gene, whereas in the other it reduced mRNA levels slightly. The telomere sequence did not induce chromosome truncation and the seeding of a new telomere at a frequency above the limits of detection. Similarly, the telomere sequence did not alter the rate or distribution of homologous recombination events. The interstitial telomere repeat sequence in both orientations, however, dramatically increased gene rearrangements some 30-fold. Analysis of individual rearrangements confirmed the involvement of the telomere sequence. These studies define the telomere repeat sequence as a destabilizing element in the interior of chromosomes in mammalian cells.

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Types, stability, and phenotypic consequences of chromosome rearrangements leading to interstitial telomeric sequences.

Abstract: Using in situ hybridisation, we identified interstitial telomeric sequences in seven chromosomal translocations present in normal and in syndromic subjects. Telo

Cited by 65 publications

References 28 publications

Molecular characterization of jumping translocations reveals spatial and temporal breakpoint heterogeneity

Molecular characterization of jumping translocations reveals spatial and temporal breakpoint heterogeneity

The preference for GT-rich DNA by the yeast Rad51 protein defines a set of universal pairing sequences

Insertion of a Telomere Repeat Sequence into a Mammalian Gene Causes Chromosome Instability

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