Alterations leading to increased ribonucleotide reductase in cells selected for resistance to deoxynucleosides

Sublines with altered ribonucleotide reductase have been isolated from the mouse fibroblast line 3T6 by selection for resistance to arabinosyl cytosine and the deoxynucleosides of adenine, thymidine, and guanine. The alterations in enzyme activity are of two kinds: (a) 4–10 fold higher levels of enzyme activity per unit of cell protein; (b) partial desensitization of the enzyme to the allosteric negative effector dATP. The combination of these two alterations keeps the reductase activity of extracts of these deoxynucleoside-resistant clones at wild type levels even in the presence of high concentrations of the deoxynucleotides. The alterations of reductase activity are stable over long periods of cultivation in the absence of deoxynucleosides, and are presumably due to mutation. Despite these changes, the reductase activity is still regulated during growth, since it is much lower in resting than in growing cells.