Transcription-based model for the induction of interchromosomal exchange events by ionizing irradiation in mammalian cell lines that undergo necrosis

Purpose: To develop a model of the molecular events leading to ionizing radiation-induced interchromosomal exchange in mammalian cells that undergo necrosis. Outline of the model: DNA double-strand breaks (DSB), primarily those involving multiple individual damage sites (i.e. complex DSB), are postulated to be the critical initiating lesion. Only those DSB occurring in transcription units that are associated with transcription factories are postulated to induce chromosomal exchange events. It is suggested that such DSB are brought into contact with a DNA topoisomerase I (topo I) molecule through RNA polymerase II (pol II)-catalysed transcription and give rise to trapped DNA-topo I cleavage complexes. Trapped complexes are postulated to interact with another topo I molecule on a temporarily inactive transcription unit at the same transcription factory leading to DNA cleavage and subsequent strand exchange between the cleavage complexes. Interchromosomal exchange events will occur when the cleavage complexes are on transcription units located on different chromosomes. Outcomes: The model can explain a variety of phenomena that includes: the increased resistance to killing by ionizing radiation shown by quiescent cells (i.e. potentially lethal damage repair); the effect of ploidy on sensitivity to killing by DSB; the effect of chasing time on sensitivity to killing by DNA-incorporated I-125 decays after pulse labelling; and the size of the target for ionizing radiation-induced cell killing.