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Molecular Nature of Ultraviolet B Light-induced Deletions in the Murine Epidermis¹

Division of Genetics and Mutagenesis, National Institute of Health Sciences, Tokyo 158-8501 [M. H., K. M., T. N.]; Division of Bioregulation Studies, Tokyo University of Agriculture, Tokyo 156-8502 [M. H., Y. K.]; and Department of Cell Biology, Tohoku University Graduate School of Medicine, Sendai 980-8575 [H. I., T. O.], Japan

Depletion of the stratospheric ozone layer leads to an increase in ambient UV loads, which are expected to raise skin cancer incidences. Tumor development in the skin could be a multistep process in which various genetic alterations, such as point mutations and deletions, occur successively. Here, we demonstrate that UVB irradiation efficiently induces deletions in the epidermis using a novel transgenic mouse, gpt delta. In this mouse model, deletions in DNA integrated in the chromosome are preferentially selected as Spi^- (sensitive to P2 interference) phages, which can then be subjected to molecular analysis. The mice were exposed to UVB at single doses of 0.3, 0.5, 1.0, 1.5, and 2.0 kJ/m². After 4 weeks, phage was rescued from the genomic DNA of the epidermis by in vitro packaging reactions. The mutant frequencies of Spi^- with large deletions in the epidermis increased >15-fold at a UVB dose of 0.5 kJ/m² over the control. Molecular sizes of most of the large deletions were >1000 bp. More than one-half of the large deletions occurred between short direct-repeat sequences from 1 to 6 bp, and the remainder had flush ends. In the unirradiated mouse, almost all of the Spi^- mutants were 1-bp frameshifts in runs of identical bases. These results suggest that UVB irradiation induces deletions in the murine epidermis, and most of the deletions are generated through end-joining of double strand breaks in DNA.

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