MECHANISMS OF RADIATION-INDUCED CHROMATID BREAKS

Chromatid breaks are thought to result from DNA double-strand breaks ( dsb) but the mechanisms are not yet understood. The early (but still p revailing) 'breakage-first' hypothesis fails to explain the large size of chromatid breaks; many of which are estimated to represent the app arent loss of between 15 and 45 Mbp (up to 30% of an average chromatid ). The alternative 'exchange' hypothesis of Revell has potential for e xplaining the large sizes of deletions, but assumes the interaction of two lesions which therefore predicts a quadratic dependence of chroma tid breaks on radiation dose. The exchange hypothesis is not tenable f or mammalian cells since chromatid breaks are observed to be induced l inearly with dose in both human and rodent cells. An alternative 'sign al' model of chromatid breaks is outlined whereby a single dsb, occurr ing within a large looped chromatin domain, is signalled (possibly by molecules such as DNAPK or ATM protein) and triggers the cell to under go a recombinational exchange, either within a chromatid or between si ster chromatids. If incomplete, such recombinational exchanges would a ppear as chromatid breaks at metaphase. It is suggested that the large looped chromatin domains could be equivalent to one or more likely se veral replication 'factories' in which the DNA processing enzymes requ ired for exchange formation would be located. (C) 1998 Elsevier Scienc e B.V. All rights reserved.