Model for the initiation of ionizing radiation-induced apoptosis in lymphoid cells by complex DNA double-strand breaks

PURPOSE: To present a model for the molecular events that lead to the induction of apoptosis in irradiated lymphoid cells based on the assumption that the process is triggered by complex DNA double-strand breaks (DSB). OUTLINE OF THE MODEL: * Cellular DNA repair mechanisms have difficulty rejoining complex DSB because of the nature of the end groups on such breaks. * Association between p53 and DNA topoisomerase I (topo I) can occur at complex DSB in open regions of the genome and the enzymic activity of such associations is not suppressed by polyADP-ribosylation. * Binding of p53 and topo I at a complex DSB results in the transient trapping of a DNA-topo I cleavage complex. * Transiently trapped DNA-topo I cleavage complexes at complex DSB are reversed following association with topo I bound elsewhere in the genome, thus initiating a misrejoining event. * Topo I-mediated DNA misrejoining creates a structure that activates p53. Initiation of rapid interphase apoptosis requires that the inducing signal from activated p53 exceeds a threshold level. * Initiation of rapid interphase apoptosis is regulated by poly(ADP-ribose) polymerase.