Model for the initiation of ionizing radiation-induced apoptosis in lymphoid cells by complex DNA double-strand breaks.
OBJECTIVE
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).
* 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.
Radford
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Sir Donald and Lady Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, St Andrews Place, East Melbourne, Victoria 3002, Australia. i.radford@pmci.unimelb.edu.au
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D002460:Cell Line; D004247:DNA / Q000378:metabolism / Q000528:radiation effects*; D004249:DNA Damage; D004260:DNA Repair; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D007399:Interphase; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D051379:Mice; D008954:Models, Biological; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; D004264:DNA Topoisomerases, Type I