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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.

Methodological problems arise on the way of radiation carcinogenesis modelling with the incorporation of radiobiological and cancer biology mechanistic data. The results of biophysical modelling of different endpoints [DNA DSB induction, repair, chromosome aberrations (CA) and cell proliferation] are presented and applied to the analysis of RBE-LET relationships for radiation-induced neoplastic transformation (RINT) of C3H/10T1/2 cells in culture. Predicted values for some endpoints correlate well with the data. It is concluded that slowly repaired DSB clusters, as well as some kind of CA, may be initiating events for RINT. As an alternative interpretation, it is possible that DNA damage can induce RINT indirectly via epigenetic process. A hypothetical epigenetic pathway for RINT is discussed.

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.