Origin of Chromosome Aberrations: Mechanisms

Abstract

After more than 60 years of observation and research, the molecular mechanisms underlying radiation-induced chromosome aberration formation are still controversial. Here I review the classical and recent models for the origin of aberrations and some of the current controversies. The experimental evidence to date strongly suggests that the mechanisms underlying the two aberration types, chromosome and chromatid aberrations, differ. It is also likely that two separate mechanisms exist for the formation of chromosome exchanges; both contributing to the overall yield. Recent evidence supports the previously postulated existence of an alternative pathway to the classical 'two-hit' mechanism for chromosome exchanges, involving interaction of two DNA double-strand breaks (DSB). This alternative pathway involves a cell's response to a single DSB, perhaps of a relatively complex nature, that interacts with DNA of an undamaged chromosome. Like chromosome aberrations, chromatid aberrations comprise both breaks and exchanges that could have different underlying mechanisms. Recent studies have focussed on the formation and origin of chromatid breaks. It is known that these breaks are formed from single DSB, but are unlikely to be formed (as has been postulated previously) simply by an expansion of the DSB. Here I argue that chromatid breaks are most likely to result from chromatin rearrangements, initiated by a DSB, but are formed by a mechanism involving misjoining of chromatin ends by topoisomerase II.