Molecular dissection of in vivo DNA rearrangements induced by radiation and chemical mutagens

Cellular DNA is continuously exposed to radiation and chemicals. To analyze the deletion mutations in a whole body system, gpt delta mice has been established. In this mouse model, deletions in lambda phage DNA integrated in the chromosome are preferentially selected as Spi− (sensitive to P2 interference) phages, which can then be subjected for molecular analysis. Here, we report the sequence characteristics of deletions induced by ionizing radiations in liver, ultraviolet light B (UVB) in epidermis, mitomycin C (MMC) in bone marrow and heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) in colon. About half of the large deletions occur between short direct-repeat sequences and the remainder had flush ends, suggesting that they are generated during the repair of double-strand breaks in DNA. Radiations, UVB and MMC efficiently induced the large deletions whereas PhIP mainly generated one base deletions in runs of guanine bases. The most predominant mutations in untreated mice were one base deletions in runs of adenine bases. Possible mechanisms of the intra-chromosomal deletion mutations are discussed.