Nuclear 3D organization and radiosensitivity

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.