Impact of genomic imprinting on genomic instability and radiation-induced mutation

Purpose: The purpose of this review is to assess the effect of radiation-in duced mutation on genes subject to genomic imprinting, and the consequences of this on the understanding of genomic instability. Genomic imprinting is the phenomenon in which one of the two alleles of a gene is expressed or s uppressed depending on the gamete from which it was inherited, thus effecti vely rendering a cell hemizygous for the expression of certain key genes. T he consequence of this is that such loci are potentially more likely target s for mutagenesis since one allele is normally inactive. This is not only i mportant in the recognition of a subgroup of target genes for radiation-ind uced damage, but also raises the possibility of mutations affecting the epi genotype of key tumour suppressor or tumour promoting genes. Such mutations may in principle affect the stability of imprinting and may fall into a no vel class of 'epimutation', where the DNA sequence is not affected, but pos t-transcriptional mechanisms of epigenotype maintenance are stably altered. These novel mechanisms are discussed in relation with radiation-induced ge nomic instability and the heritability of tumour predisposition from radiat ion-exposed parents. Conclusions: As yet there is only circumstantial evidence that the targets for radiation-induced DNA and epigenetic damage are imprinted genes, or gen es involved in the maintenance of the epigenotype. However, the potential c onsequences of such genes being important targets for the generation of gen omic instability or other forms of damage are serious and could affect the interpretation of the risks of low dose radiation exposure and of epidemiol ogical data.