Centromeric inactivation in a dicentric human Y;21 translocation chromosome

Fisher, Andrew M.; Al‐Gazali, Lihadh; Pramathan, Thachillath; Quaife, R; Cockwell, Annette E.; Barber, John; Earnshaw, William C.; Axelman, Joyce; Migeon, Barbara R.; Tyler‐Smith, Chris

doi:10.1007/s004120050240

Cited by 38 publications

(32 citation statements)

References 39 publications

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“…A likely explanation for this is that dicentric chromosomes are unstable. These products can comigrate to the same pole during mitosis (38,87,102), inactivate one of the centromeres (2,12,32,39,102), or undergo additional cycles of rearrangements during mitosis (59,60,65,67). Checkpoint defects would allow cells to progress through the cell cycle in the presence of such broken chromosomes.…”

Section: Discussionmentioning

confidence: 99%

Saccharomyces cerevisiae as a Model System To Define the Chromosomal Instability Phenotype

Putnam

Pennaneach

Kolodner

2005

Molecular and Cellular Biology

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Translocations, deletions, and chromosome fusions are frequent events seen in cancers with genome instability. Here we analyzed 358 genome rearrangements generated in Saccharomyces cerevisiae selected by the loss of the nonessential terminal segment of chromosome V. The rearrangements appeared to be generated by both nonhomologous end joining and homologous recombination and targeted all chromosomes. Fifteen percent of the rearrangements occurred independently more than once. High levels of specific classes of rearrangements were isolated from strains with specific mutations: translocations to Ty elements were increased in telomerasedefective mutants, potential dicentric translocations and dicentric isochromosomes were associated with cell cycle checkpoint defects, chromosome fusions were frequent in strains with both telomerase and cell cycle checkpoint defects, and translocations to homolog genes were seen in strains with defects allowing homoeologous recombination. An analysis of human cancer-associated rearrangements revealed parallels to the effects that strain genotypes have on classes of rearrangement in S. cerevisiae.The development and progression of cancer are correlated with genetic instability. These genomic changes are associated with either a microsatellite instability (MSI) phenotype, involving defects in mismatch repair and a dramatic increase in base substitution and insertion/deletion mutation rates, or a chromosomal instability (CIN) phenotype, involving changes in chromosome number and structure (reviewed in reference 55); however, some tumors have been observed with both MSI and CIN. A causal role for CIN in tumorigenesis is still debated; however, most cancers are associated with dramatic changes to the chromosomal complement (68), and several hereditary cancer predisposition syndromes are closely linked to CIN (49). Using the mutator hypothesis (61), it has been argued that changes in gene dosage, a loss of heterozygosity, a deregulation of gene expression, and the generation of gain-of-function protein chimeras due to CIN are sufficient to drive tumorigenesis in many cases, even without mutations in oncogenes or tumor suppressor genes (29). Thus, understanding CIN is likely to provide some insight into the mechanisms of tumorigenesis.One of the major barriers to understanding the CIN phenotype, even for model organisms such as the yeast Saccharomyces cerevisiae, is that there are very few genetic systems capable of systematic characterizations of genome rearrangements (49, 105). In principle, rearrangements can arise through both homologous recombination (HR) and nonhomologous end-joining (NHEJ) pathways. In practice, the lack of a detailed understanding of the genetic and biochemical mechanisms that underlie these types of rearrangements in vivo has remained a bottleneck to understanding the generation of genome rearrangements in cancer and other human diseases.An assay designed to analyze the formation of translocations and other gross chromosomal rearrangements (GCRs) was developed wit...

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Section: Discussionmentioning

confidence: 99%

Saccharomyces cerevisiae as a Model System To Define the Chromosomal Instability Phenotype

Putnam

Pennaneach

Kolodner

2005

Molecular and Cellular Biology

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“…Epigenetic modifications might differentiate the 180-bp repeat clusters. Inactivation of one centromere on dicentric chromosomes has been reported for humans (27,28), maize (29), and for barley centromeres in wheat chromosomes (30). Although the mechanism of centromere inactivation remains unclear, these phenomena imply that the DNA sequences alone are insufficient to trigger inactivation and that epigenetic marks are necessary for maintaining centromere function.…”

Section: As Indicated By Mcclintockmentioning

confidence: 99%

Functional analysis of theArabidopsiscentromere by T-DNA insertion-induced centromere breakage

Murata

Yokota

Shibata

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Two minichromosomes (␣ and ␦) in addition to two other aberrant chromosomes (␤ and ␥) were found in a transgenic Arabidopsis plant produced by an in planta vacuum infiltration technique. The minichromosomes were successfully separated by successive crossing and selfing and added to wild-type Columbia (Col-0) as a supernumerary chromosome. FISH indicated that both of the two minichromosomes originated from the short arm of chromosome 2. The mini ␣ chromosome contained the whole short-arm 2S and a truncated centromere (180-bp repeat cluster), whereas mini ␦ lacked the terminal region including telomere repeats. Pachytene FISH clearly revealed that mini ␦ comprised a ring chromosome carrying two copies of the region from the 180-bp repeat cluster to BAC-F3C11. Both of the 180-bp clusters (each Ϸ500 kb in length) were thought to possess normal centromere functions because the centromere-specific histone H3 variant (HTR12) was detected on both clusters. Notwithstanding this dicentric and ring form, mini ␦ was stably transmitted to the next generations, perhaps because of its compact size (<4 Mb). Chromosome ␤ also comprised a dicentric-like structure, with one of the two 180-bp repeat sites derived from chromosome 1 and the other from chromosome 2. However, the latter was quite small and failed to bind HTR12. The data obtained in this study indicated that 500 kb of the 180-bp array of the chromosome 2 centromere, from the edge of the 180-bp array on the short-arm side, is sufficient to form a functional domain.minichromosomes ͉ ring chromosome

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“…However, the presence of alphoid DNA is not sufficient to create a functional centromere structure. On stable dicentric chromosomes, CENP-A, CENP-C and CENP-E [a kinesin-like motor protein found at the kinetochore (Yen et al, 1991;Wood et al, 1997)] do not assemble on the inactive centromere despite the presence of alphoid DNA and CENP-B (Sullivan and Schwartz, 1995;Warburton et al, 1997;Fisher et al, 1997). A marker chromosome containing a neocentromere, which lacks detectable alphoid DNA and CENP-B (du Sart et al, 1997), was found to be mitotically stable, and most of the known centromere proteins assembled at the site of the neocentromere (Saffery et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic assembly of centromeric chromatin at ectopic α-satellite sites on human chromosomes

Nakano

Okamoto

Ohzeki

et al. 2003

Journal of Cell Science

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To investigate the mechanism of chromatin assembly at human centromeres, we isolated cultured human cell lines in which a transfected alpha-satellite (alphoid) YAC was integrated ectopically into the terminal region of host chromosome 16, where it was stably maintained. Centromere activity of the alphoid YAC was suppressed at ectopic locations on the host chromosome, as indicated by the absent or reduced assembly of CENP-A and -C. However, long-term culture in selective medium, or shortterm treatment with the histone deacetylase inhibitor Trichostatin A (TSA), promoted the re-assembly of CENP-A, -B and -C at the YAC site and the release of minichromosomes containing the YAC integration site. Chromatin immunoprecipitation analyses of the re-formed minichromosome and the alphoid YAC-based stable human artificial chromosome both indicated that CENP-A and CENP-B assembled only on the inserted alphoid array but not on the YAC arms. On the YAC arms at the alphoid YAC integration sites, TSA treatment increased both the acetylation level of histone H3 and the transcriptional level of a marker gene. An increase in the level of transcription was also observed after long-term culture in selective medium. These activities, which are associated with changes in chromatin structure, might reverse the suppressed chromatin state of the YAC at ectopic loci, and thus might be involved in the epigenetic change of silent centromeres on ectopic alphoid loci.

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Centromeric inactivation in a dicentric human Y;21 translocation chromosome

Cited by 38 publications

References 39 publications

Saccharomyces cerevisiae as a Model System To Define the Chromosomal Instability Phenotype

Saccharomyces cerevisiae as a Model System To Define the Chromosomal Instability Phenotype

Functional analysis of theArabidopsiscentromere by T-DNA insertion-induced centromere breakage

Epigenetic assembly of centromeric chromatin at ectopic α-satellite sites on human chromosomes

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