Developmental Modifications Induced by DNA Base Analogs

Abstract

Pulse treatment of Drosophita melanogasler larvae with thymidine analogs in the presence of inhibitors of thymidylate synthetase activity induces a variety of growth lesions in the adult flies. We determined the frequency of the developmental lesions induced for a variety of treatment conditions and examined the incorporation of the analogs into DNA of larvae treated in a similar manner for each of these conditions. Lesion induction is correlated with bromodeoxyundine incorporation into DNA. The distribution of incorporated bromodeoxyuridine in the pyrimidine oligonucleotides released from DNA by formic acid-diphenylamine hydrolysis was compared with the incorporation pattern of exogenous thymidine. This comparison shows that bromodeoxyuridine is not randomly accepted at all thymine sites for incorporation into DNA under the feeding conditions used in these experiments. There were also differences between the patterns of bromodeoxyuridine- incorporated DNAs from larvae receiving the analog under conditions slightly effective and highly effective for morphogenic lesions. Examination of the size and frequency of lesions as a function of larval age at the time of treatment indicates there is a clonal pattern of propagation of the analog-affected cells. Since several cell generations separate the analog pulse and the time of eventual differentiation of the imaginal discs, we conclude that following the incorporation of bromodeoxyuridine into morphogenically critical base sequences of DNA, a cell undergoes an informational change that is transmitted to its progeny cells which differentiate during metamorphosis as a cluster of phenotypically altered cells. The presence of bromodeoxyuridine per se in each cell of a clone is not necessary for expression of the altered patterns of differentiation.