Involvement of ribonucleotide reductase in cellular differentiation

L₆ and L₈ rat myoblast cell lines have been selected for resistance to hydroxyurea, an antineoplastic agent whose intracellular target is the rate-limiting enzyme activity of DNA synthesis, ribonucleotide reductase. In contrast to the differentiation-competent parental lines from which they were selected, the drug-resistant lines exhibit a grossly altered or absent myogenic capacity. Independent selections have revealed a strong correlation between changes in ribonucleotide reductase, as determined by velocity levels and product pool analyses, and altered myogenic potential. These results provide the first indication that alterations in this key enzyme activity and its accompanying deoxyribonucleoside triphosphate pools can affect cellular differentiation.