Higher-order structure of interphase chromosomes and radiation-induced chromosomal exchange aberrations

Ostashevsky, Joseph Y.

doi:10.1080/09553000050134410

Cited by 26 publications

(16 citation statements)

References 42 publications

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“…The value of the interaction distance d was fixed at 1.5 Ìm on the basis of the average distance between the mass centres of two neighbouring chromosome territories (see below). This number is consistent with values adopted by other authors with different modelling approaches (Kellerer, 1985;Savage, 1996;Ostashevsky, 2000;Sachs et al, 2000a).…”

Section: Assumptionssupporting

confidence: 81%

Models of chromosome aberration induction: an example based on radiation track structure

Ballarini

Ottolenghi²

2004

Cytogenet Genome Res

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A few examples of models of chromosome aberration induction are summarised and discussed on the basis of the three main theories of aberration formation, that is “breakage-and-reunion”, “exchange” and “one-hit”. A model and code developed at the Universities of Milan and Pavia is then presented in detail. The model provides dose-response curves for different aberration types (dicentrics, translocations, rings, complex exchanges and deletions) induced in human lymphocytes by gamma rays, protons and alpha particles of different energies, both as monochromatic fields and as mixed fields. The main assumptions are that only clustered – and thus severe – DNA breaks (“Complex Lesions”, CL) can participate in the production of aberrations, and that only break free ends in neighbouring chromosome territories can interact and form exchanges. The yields of CLs induced by the various radiation types of interest are taken from a previous modelling work. These lesions are distributed within a sphere representing the cell nucleus according to the radiation track structure, e.g. randomly for gamma rays and along straight lines for light ions. Interphase chromosome territories are explicitly simulated and configurations are obtained in which each chromosome occupies an intranuclear domain with volume proportional to its DNA content. In order to allow direct comparisons with experimental data, small fragments can be neglected since usually they cannot be detected in experiments. The presence of a background level of aberrations is also taken into account. The results of the simulations are in good agreement with experimental dose-response curves available in the literature, that provides a validation of the model both in terms of the adopted assumptions and in terms of the simulation techniques. To address the question of “true” incompleteness, simulations were also run in which all fragments were assumed to be visible.

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Section: Assumptionssupporting

confidence: 81%

Models of chromosome aberration induction: an example based on radiation track structure

Ballarini

Ottolenghi²

2004

Cytogenet Genome Res

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“…In addition, it is in keeping with what is understood about chromatin loop organisation and movement constraints (Marshall et al, 1997;Masuzawa et al, 2000;Ostashevsky, 2000;Edelmann et al, 2001). It is possible however that the scope for such movement may be greater after ·-particle radiation, compared to low-LET radiations, due to the observed longer average lifetimes of dsb from high-LET radiations (Pastwa et al, 2003).…”

Section: Discussionmentioning

confidence: 50%

Increased complexity of radiation-induced chromosome aberrations consistent with a mechanism of sequential formation

Anderson¹,

Papworth²,

Stevens³

et al. 2005

Cytogenet Genome Res

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Complex chromosome aberrations (any exchange involving three or more breaks in two or more chromosomes) are effectively induced in peripheral blood lymphocytes (PBL) after exposure to low doses (mostly single particles) of densely ionising high-linear energy transfer (LET) α-particle radiation. The complexity, when observed by multiplex fluorescence in situ hybridisation (m-FISH), shows that commonly four but up to eight different chromosomes can be involved in each rearrangement. Given the territorial organisation of chromosomes in interphase and that only a very small fraction of the nucleus is irradiated by each α-particle traversal, the aim of this study is to address how aberrations of such complexity can be formed. To do this, we applied theoretical “cycle” analyses using m-FISH paint detail of PBL in their first cell division after exposure to high-LET α-particles. In brief, “cycle” analysis deconstructs the aberration “observed” by m-FISH to make predictions as to how it could have been formed in interphase. We propose from this that individual high-LET α-particle-induced complex aberrations may be formed by the misrepair of damaged chromatin in single physical “sites” within the nucleus, where each “site” is consistent with an “area” corresponding to the interface of two to three different chromosome territories. Limited migration of damaged chromatin is “allowed” within this “area”. Complex aberrations of increased size, reflecting the path of α-particle nuclear intersection, are formed through the sequential linking of these individual sites by the involvement of common chromosomes.

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Section: Introductionmentioning

confidence: 99%

“…Recent evidence suggests that interphase chromatin is organized in large loops, several megabase pair in size Yokota et al, 1995;Ostashevsky, 1998). While within each loop chromatin is randomly folded, specific loop-attachment sites may impose a constrained backbone structure (Yokota et al, 1995;Marshall et al, 1997;Ostashevsky, 1998Ostashevsky, , 2000Cremer et al, 2000).At present, it is well established that both mitotic chromosomes and interphase chromatin are composed of distinct functional domains (for recent reviews, see Cockell and Gasser, 1999;Belmont et al, 1999;Cremer et al, 2000). Each domain occupies a specific spatial position and replicates at a precise time during S phase.…”

mentioning

confidence: 99%

Chromosomal G-dark Bands Determine the Spatial Organization of Centromeric Heterochromatin in the Nucleus

Carvalho

Pereira

Ferreira

et al. 2001

MBoC

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Gene expression can be silenced by proximity to heterochromatin blocks containing centromeric ␣-satellite DNA. This has been shown experimentally through cis-acting chromosome rearrangements resulting in linear genomic proximity, or through trans-acting changes resulting in intranuclear spatial proximity. Although it has long been been established that centromeres are nonrandomly distributed during interphase, little is known of what determines the three-dimensional organization of these silencing domains in the nucleus. Here, we propose a model that predicts the intranuclear positioning of centromeric heterochromatin for each individual chromosome. With the use of fluorescence in situ hybridization and confocal microscopy, we show that the distribution of centromeric ␣-satellite DNA in human lymphoid cells synchronized at G 0 /G 1 is unique for most individual chromosomes. Regression analysis reveals a tight correlation between nuclear distribution of centromeric ␣-satellite DNA and the presence of G-dark bands in the corresponding chromosome. Centromeres surrounded by G-dark bands are preferentially located at the nuclear periphery, whereas centromeres of chromosomes with a lower content of G-dark bands tend to be localized at the nucleolus. Consistent with the model, a t(11; 14) translocation that removes G-dark bands from chromosome 11 causes a repositioning of the centromere, which becomes less frequently localized at the nuclear periphery and more frequently associated with the nucleolus. The data suggest that "chromosomal environment" plays a key role in the intranuclear organization of centromeric heterochromatin. Our model further predicts that facultative heterochromatinization of distinct genomic regions may contribute to cell-type specific patterns of centromere localization. INTRODUCTIONHow are genomes organized in the nucleus, and what is the role of genome organization on cellular functions? These fundamental questions in cell biology are attracting increased attention as the genomes of higher eukaryotes are being sequenced. Diverse models, ranging from highly random to highly organized, have been proposed for the organization of interphase chromatin (for reviews see Manuelidis, 1990;Haaf and Schmid, 1991;Cremer et al., 1993). Recent evidence suggests that interphase chromatin is organized in large loops, several megabase pair in size Yokota et al., 1995;Ostashevsky, 1998). While within each loop chromatin is randomly folded, specific loop-attachment sites may impose a constrained backbone structure (Yokota et al., 1995;Marshall et al., 1997;Ostashevsky, 1998Ostashevsky, , 2000Cremer et al., 2000).At present, it is well established that both mitotic chromosomes and interphase chromatin are composed of distinct functional domains (for recent reviews, see Cockell and Gasser, 1999;Belmont et al., 1999;Cremer et al., 2000). Each domain occupies a specific spatial position and replicates at a precise time during S phase. In metaphase chromosomes, the domains are identified as alternate transverse bands...

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Higher-order structure of interphase chromosomes and radiation-induced chromosomal exchange aberrations

Cited by 26 publications

References 42 publications

Models of chromosome aberration induction: an example based on radiation track structure

Models of chromosome aberration induction: an example based on radiation track structure

Increased complexity of radiation-induced chromosome aberrations consistent with a mechanism of sequential formation

Chromosomal G-dark Bands Determine the Spatial Organization of Centromeric Heterochromatin in the Nucleus

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