Spatial organization of the mouse chromosomes influences the landscape of intrachromosomal exchange aberration breakpoints

Abstract

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.