Radiation-Induced Mitotic Recombination in Human Lymphoblastoid Cells

摘要

Diploid organisms express their full range of phenotypes only through the sexual cycle, because newly acquired traits are more often recessive than dominant. However, somatic cells do not go through a haploid phase and mating, and simple fusion between diploid cells does not lead to expression of recessive phenotypes. It has been widely accepted that carcinogenesis requires in its multistage process the mechanisms through which malignant cells express their recessive mutant phenotypes in high frequency, especially for tumour suppressor genes. In addition to a new point mutation in a wild-type allele, the putative mechanisms for expression of a recessive phenotype include loss of a wild-type allele due to deletion, mitotic recombination, gene conversion, non-disjunction and reduplication. Particularly the involvement of mitotic recombination due to somatic crossing over in carcinogenesis was hypothesised for the first time by Ohno a quarter century ago. Evidence for in vivo occurrence of mitotic recombination involving glycophorin A locus and also that for the HLA-A locus have actually been obtained with erythrocytes and lymphocytes, respectively, from atomic bomb survivors and patients with Bloom's syndrome. APRT catalyses phosphorylation of adenine. The enzyme is encoded by a gene of 2.3 kb in length on the long arm of the chromosome 16. By using a lymphoblastoid cell line in which one APRT allele had nonsense mutation at exon 3, we have been characterising the second step of loss-of-function mutations and determining the relative contribution of each mechanism leading to allelic losses. The mode of radiation-induced mutational events resembled that reported for tumour suppressor genes in malignancies in that mitotic recombination as well as deletion prevailed, although mitotic non-disjunction (a whole chromosome loss) with reduplication turned out to be undetected in this APRT mutation assay system.