[The Main Target of Carcinogenesis Is Not DNA]

The first target of radiation carcinogenesis is thought to be DNA. However, this has not been demonstrated for radiation carcinogenesis. We found that the frequency of aneuploid cells was closely related to that of radiation-induced cell transformation and natural cell transformation by high-density cultivation, but the frequency of gene mutations was not. Cells containing a functional p53 gene become tetraploid, but do not exhibit tumorigenicity. In contrast, cells without a functional p53 gene readily become triploid and acquire tumorigenicity. Both radiation exposure and high-density cultivation elevated the level of intracellular oxidative radicals. One of these radicals, such as long-lived radical, induced centrosome destabilization and produced cells carrying extra centrosomes, which together promote merotelic attachment of the chromosome by altering spindle geometry. Unresolved merotelic attachments can give rise to lagging chromosomes during anaphase. Aneuploidy was observed at high frequency in the early stages of cell transformation. These results strongly suggest that the main target in carcinogenesis induced by low-dose radiation is not DNA, but is rather the centrosomes, which are proteins involved in the chromosomal homeostasis maintenance mechanism. In addition, the route of radiation carcinogenesis may be the same as that of natural carcinogenesis.