The formation of short DNA fragments, up to 3 kbp, induced in chromatin by nitrogen (LET 97 keV/mм) and iron (LET 190 keV/mм) ions was studied by computer simulation. Chromatin models with different structure parameters and Monte Carlo track structure simulation were used to assess the impact of chromatin fiber structure and LET on the DNA fragment size distribution. For the structures modeled (different types of solenoids, a chain of nucleosomes), the fragment size distribution had a maximum in the region of ~100 bp corresponding to the formation of DNA breaks in two neighboring turns of the helix on the nucleosome. The calculation predicted the peak in the region of ~1000 bp, corresponding to the formation of DNA breaks in two neighboring turns of the solenoid, which parameters depended on the degree of compactness of the fiber and were independent of LET. The assumption was introduced of the presence of subpopulations of various chromatin structures under irradiation. It allowed to explain the experimentally observed size distributions of the short DNA fragments induced by high-LET charged particles.

The long-standing question in radiation and cancer biology is how principles of chromosome organization impact the formation of chromosomal aberrations (CAs). To address this issue, we developed a physical modeling approach and analyzed high-throughput genomic data from chromosome conformation capture (Hi-C) and translocation sequencing (HTGTS) methods. Combining modeling of chromosome structure and of chromosomal aberrations induced by ionizing radiation (IR) and nuclease we made predictions which quantitatively correlated with key experimental findings in mouse chromosomes: chromosome contact maps, high frequency of cis-translocation breakpoints far outside of the site of nuclease-induced DNA double-strand breaks (DSBs), the distinct shape of breakpoint distribution in chromosomes with different 3D organizations. These correlations support the heteropolymer globule principle of chromosome organization in G1-arrested pro-B mouse cells. The joint analysis of Hi-C, HTGTS and physical modeling data offers mechanistic insight into how chromosome structure heterogeneity, globular folding and lesion dynamics drive IR-recurrent CAs. The results provide the biophysical and computational basis for the analysis of chromosome aberration landscape under IR and nuclease-induced DSBs.

How 3D chromosome organization affects chromosomal aberrations is an important unresolved question in cell and radiation biology. In interphase the chromosomes form territories where chromatin folds into quite heterogeneous states. The mechanisms determining the spectrum of chromosome conformations remain poorly understood. We introduced the polymer model of mouse chromosome and generated the ensemble of 3D conformations. The chromosome model was validated against independent Hi-C (high-throughput chromosome conformation capture) data. The model described well Hi-C contact heatmap for chromosome 18 in pro-B mouse cells, both ATM-deficient and wild-type. We used the chromosome model to assess the role of chromosome structure in breakpoint distribution for intrachromosomal exchange aberrations. We investigated the effect of elevated frequency of breakpoints outside of the region of enzymatic breaksite. Chromosome aberration model explained breakpoint distribution under recurrent and ionizing radiation-induced DNA double-strand breaks in mouse chromosome 18 on the basis of contact-first mechanism. Overall, our results provide a framework for assessment of role of chromosome 3D organization on chromosome aberrations following DNA damage of different origin.

The explanation for the compartmentalization of the chromosome contact maps observed by Hi-C method is still an unsolved mystery. The most natural and generally accepted explanation is that blocks of frequent/rare contacts on the entire map are associated with the existence of blocks of homogeneous elements along the chromosome that interact in 3D so that elements of the same type interact frequently and those of different types rarely. We study the polymer model of the chromosome, in which there are neither blocks of homogeneous elements nor homogeneous interactions and all the interaction energies are different. We demonstrate that such a heteropolymer model is able to describe chromosomal maps with high accuracy. The differences from compartment polymer models of chromosomes, which actually reflect the mechanism of microphase separation in polymers, are discussed further.

In this paper, changes in a large-scale 3D structure of chromosomes during stem cell differentiation is studied. The polymer coarse-grained model of a human interphase chromosome is introduced which reproduces the experimental Hi-C contact maps in chromosomes 12, 17 for both embryonic stem and differentiated cells with high accuracy. Model based analysis of Hi-C data suggests a mechanism of establishment of preferential long-range chromosomal contacts and compartmentalization replacement during cell stem differentiation. The model provides the conceptual basis for integration of data on the dynamics of chromatin interactions, the 3D structure of chromosomes and gene expression during stem cell differentiation or reprogramming.

The origin of dose-response curves for radiation-induced chromosomal instability (CI) is studied using the mechanistic CI model. The model takes into account DNA damage generation and repair in the progeny of irradiated cells and cell passage through mitotic cycle. We consider the formation of DNA double-strand breaks (DSBs) de novo in the S phase, where predominantly chromatid-type aberrations are formed. Among them sister chromatid exchanges of the isochromatid deletion type, or chromatid dicentrics are of primary interest. When the cell enters mitosis, the fate of chromosomal aberrations depends on their types. Chromosomal and chromatid fragments, having entered mitosis, either are transmitted into one of the daughter cells, or are lost. A chromatid dicentric in mitosis forms an anaphase bridge. These mechanistic assumptions were used to demonstrate that the dose-response curves are closely related to the dynamic curves for CI. The principles underlying this relationship are analyzed.

We present a polymer modeling approach to generate the ensemble of 3D chromosome conformations at different time points of mitosis-interphase transition. Dynamics of structure during mitosis-G1 transition indicates quick and slow stages of chromosome shape alterations. At intermediate and late time scale the changes in chromosome compaction are small. To assess time dependence of contact map establishment during G1 we calculate contact maps at different times after mitotic decondensation. We demonstrate that the patterns of contacts observed soon after mitotic decondensation remain similar during G1. Whole contact map for mouse chromosome 18 at late G1 time correlates with the experimental chromosome conformation capture data. The simulations reproduce the main experimental findings, contact map persistence during G1 as well as specific pattern of long-range interactions in interphase chromosome. Our results suggest that spatial compartmentalization of an interphase chromosome is driven by interactions between different types of megabase sized chromatin domains during the formation of globular chromosome state at the end of mitotis to G1 transition.

The experimental observations demonstrate that different cell lines reveal various shape of dynamic curves for radiation-induced chromosomal instability (RICI). We analyzed our own and published data on RICI for three cell lines, CHO-K1, V79 and TK6, on the basis of the mechanistic RICI model. We demonstrate that all three dynamic curves can be successfully described by the proposed model with partially cell line specific parameters.

The question of to what extent large scale structure of interphase chromosomes contributes to chromosomal exchange aberrations is discussed for a long time but still remains unclear. We designed the polymer model of 3D organization of a mouse chromosome and simulated X-ray induced chromosomal aberrations exploring two alternative hypotheses: the probability of contacted damaged loci entailing a chromosomal rearrangement is (a) a constant value or (b) not constant, depending on the distribution of DNAsel-hypersensitivity peaks along the chromosome. The latter hypothesis proved to explain the experimental data better than the former, meaning that not only large-scale structure but also local chromatin alterations play a role.

Different cell lines demonstrate various dose response for radiation-induced chromosomal instability (RICI). To clarify the origin of differences we analyzed own and published data on RICI for four cell lines, V79, TK6, WTK1 and CHO-K1 on the basis of the mechanistic RICI model. We conclude that observable dose-response shapes, both plateau-like and strong dose dependent behavior, may be jointly explained by the same model of RICI. Mechanistic modeling reveals that a variation of certain set of RICI parameters leads to strong modification of dose-response curve.

Current mechanisms of radiation-induced chromosomal aberration (CA) formation suggest misrepair of chromosomal lesions being in spatial proximity. In this case CAs have to depend on pattern of chromosomal contacts and on chromosome spatial organization in a cell nucleus. We were interested in whether variation of nucleus 3D organization results in difference of radiation induced CA formation frequency. Experimental data available do not provide information sufficient for definite conclusions. To have more deep insight in this issue we developed the biophysical modeling technique taking into account different levels of chromosome/nuclear organization and radiation damage of DNA and chromosomes. Computer experiments on gamma irradiation were carried out for two types of cells with different 3D organization of nuclei, preferentially peripheral and internal. CA frequencies were found to depend on spatial positioning of chromosomes within a nucleus which determines a pattern of interchromosomal contacts. For individual chromosomes this effect can be more pronounced than for genome averaged. Since significant part of aberrations, for example dicentrics, results in cell death, the proposed technique is capable of evaluating radiosensitivity of cells, both normal and cancer, with the incorporation of 3D genome information. This predictive technology allows to reduce uncertainties of prognosis of biological effects of radiation compared to phenomenological methods and may have variety of biomedical applications, in particular, in cancer radiation therapy.

The origin of dose-response curves for radiation-induced chromosomal instability (CI) is studied using the mechanistic CI model. The model takes into account DNA damage generation and repair in the progeny of irradiated cells, cell passage through mitotic cycle, and intercellular signaling. It is shown that the dose-response curves are closely related to the dynamic curves. The principles underlying this relationship are analyzed.

The progress in experimental techniques aimed at 3D genome study is yet to bring about revelation of basic principles of genome folding. Chromosome conformation capture Hi-C technologies provide genome wide mapping of genomic loci interactions but spatial organization of chromosomes remains unknown. Here, we develop a polymer modeling approach to generate the ensemble of 3D chromosome conformations for mapping genetic loci contacts and the positions of megabase chromosomal domains in interphase chromosome at different time of mitosis-interphase transition. We demonstrate that (*) whole chromosome contact map (interactome) generated for mouse chromosome 18 structure and (**) contact patterns, observed soon after mitotic decondensation and remaining similar during G1, correlate well with the experimental Hi-C contact data. The results suggest that contact map formation and spatial compartmentalization of an interphase chromosome are driven by interactions between different types of domains during formation of globular chromosome state at the end of mitotis-G1 transition.

Remodeling of nuclear organization occurs during normal cell development, differentiation and cancer. One of the biggest gaps of knowledge remains how to link the information on chromatin and chromosome structural organization with genes activity. In this paper we introduce some physical ideas and a general computational method demonstrating how genome 3D architecture and its remodeling can be quantitatively modeled. We study a hypothetical scenario of alterations of chromosome territories positioning in the course of cell proliferation. On this basis we obtain quantitative information about chromosomal contacts in the nucleus. We predict changes of radial distributions of contacts between chromosomal megabase domains during proliferation. The proposed modeling approach may be helpful in integrating experimental data on nuclear reorganization associated with normal development and with various diseases. This predictive modeling may find applications in genome research of normal and cancer cells, stem cell biology, biology of aging, etc.

Radiation-induced chromosomal exchange aberrations (CAs) are formed presumably at contacts of damaged chromosomal loci. For sparsely ionizing radiation, distribution of aberrations along the chromosome should depend on distribution of contacts, i.e. on 3D organization of the chromosome. The progress in experimental techniques for study of chromosomal contacts and for precise localization of aberration breakpoints allows to verify contacts-based mechanisms of CA formation experimentally. In the present work, the polymer model of mouse interphase chromosome 18 is developed. On this basis the experimental data on contacts and aberrations are jointly analyzed. We demonstrate high correlation between chromosomal contacts and aberrations breakpoint distributions. Possible factors and alternative mechanisms which could modify breakpoint distributions are discussed.

Experiments with full-colour mFISH chromosome painting have revealed high yield of radiation-induced complex chromosomal aberrations (CAs). The ratio of complex to simple aberrations is dependent on cell type and linear energy transfer. Theoretical analysis has demonstrated that the mechanism of CA formation as a result of interaction between lesions at a surface of chromosome territories does not explain high complexes-to-simples ratio in human lymphocytes. The possible origin of high yields of γ-induced complex CAs was investigated in the present work by computer simulation. CAs were studied on the basis of chromosome structure and dynamics modelling and the hypothesis of CA formation on nuclear centres. The spatial organisation of all chromosomes in a human interphase nucleus was predicted by simulation of mitosis-to-interphase chromosome structure transition. Two scenarios of CA formation were analysed, 'static' (existing in a nucleus prior to irradiation) centres and 'dynamic' (formed in response to irradiation) centres. The modelling results reveal that under certain conditions, both scenarios explain quantitatively the dose-response relationships for both simple and complex γ-induced interchromosomal exchanges observed by mFISH chromosome painting in the first post-irradiation mitosis in human lymphocytes.

The knowledge of radiation-induced chromosomal aberration (CA) mechanisms is required in many fields of radiation genetics, radiation biology, biodosimetry, etc. However, these mechanisms are yet to be quantitatively characterised. One of the reasons is that the relationships between primary lesions of DNA/chromatin/chromosomes and dose-response curves for CA are unknown because the pathways of lesion interactions in an interphase nucleus are currently inaccessible for direct experimental observation. This article aims for the comparative analysis of two principally different scenarios of formation of simple and complex interchromosomal exchange aberrations: by lesion interactions at chromosome territories’ surface vs. in the whole space of the nucleus. The analysis was based on quantitative mechanistic modelling of different levels of structures and processes involved in CA formation: chromosome structure in an interphase nucleus, induction, repair and interactions of DNA lesions. It was shown that the restricted diffusion of chromosomal loci, predicted by computational modelling of chromosome organization, results in lesion interactions in the whole space of the nucleus being impossible. At the same time, predicted features of subchromosomal dynamics agrees well with in vivo observations and does not contradict the mechanism of CA formation at the surface of chromosome territories. On the other hand, the “surface mechanism” of CA formation, despite having certain qualities, proved to be insufficient to explain high frequency of complex exchange aberrations observed by mFISH technique. The alternative mechanism, CA formation on nuclear centres is expected to be sufficient to explain frequent complex exchanges.