Genomic instability induced by non-DSBs type of damage

Ionizing radiation induces genomic instability in the progeny of irradiated cells that have divided several to a few dozen times. The evidence has been accumulated to suggest that induction of DNA double-strand breaks (DSBs) and subsequent repair process play a key role in inducing genomic instability. In the present study, we hypothesize that some DNA lesions, but not DSBs per se, are also involved in inducing genomic instability, and ask whether oxidative base damage could induce genomic instability. We adopted UVA as an irradiation source because it generates mainly oxidative base damage but a small amount of DSBs. To study a role of oxidative damage in the induction of chromosomal instability, we transferred an UVA-irradiated human chromosome 21 into unirradiated mouse m5S cells derived from mouse fibroblasts, using a microcell-mediated chromosome transfer. The stability of UVA-irradiated chromosome was analyzed by the Whole Chromosome Painting Fluorescence in situ Hybridization (WCP-FISH) with a specific probe for human chromosome 21. Mouse cells that were transferred with unirradiated human chromosome remained diploid. However, in cells that were transferred with a UVA (4000kJ/m²) irradiated human chromosomes, we found that the recipient mouse cells became polyploid and that structural aberrations occurred not only in the UVA-irradiated human chromosomes but also in the unirradiated mouse chromosomes. These results suggest that the chromosome irradiated with UVA has a potential to become unstable by itself and induce instability in unaffected chromosomes.