Indirect mechanisms of radiation induced genomic instability at repeat loci

Radiation triggers genomic instability which results in induction of untargeted mutation and delayed mutation. The radiation induced genomic instability has been studied mostly in tissue culture cells, but analyses have also been conducted in whole body systems in which repeat sequences are frequently used as markers of mutations. The past studies on radiation induced tandem repeat mutations yielded conflicting results and the lack of knowledge of the mechanisms hampers the interpretation of the results. In this article, some of the existing controversies of genomic instability are discussed in relation to the mechanism of repeat mutation. Analyses of published and unpublished studies suggest a mechanistic similarity between radiation-induced genomic instability at repeat loci and dynamic mutations of triplet repeats. Repeat sequences are well known to block progression of replication forks which are frequently resolved by recombination between sister chromatids. Irradiation of cells induces p53 dependent S checkpoint which can promote recombination mediated repeat mutations. Thus, genomic instability at repeat loci can be viewed as a consequence of cellular attempts to restore the stability of replication in the face of the stalled replication fork; this process can be induced either spontaneously or after irradiation.