Regulation of ribonucleotide reductase activity in mammalian cells

Mammalian ribonucleotide reductase catalyzes the rate-limiting for the de novo synthesis 2'-deoxyribonucleoside 5'-triphosphates. There is some suggestion that this step may also be the rate-limiting step of DNA synthesis. It is apparent that the level of the enzyme, ribonucleotide reductase, varies through the cell cycle and is highest in those tissues with the greatest proliferation rate. This increase in activity is associated with increased protein synthesis. The purified enzyme has been shown to be subject to strict allosteric regulation by the various nucleoside triphosphates and it has been proposed that allosteric regulation plays an important role in the level of ribonucleotide reductase activity which is expressed. All experimental data relating to this point, however, do not support the role of deoxyribonucleoside triphosphates as a major factor in determining cellular reductase activity during normal cell division. Several naturally occurring factors have been isolated from cells which lower ribonucleotide reductase activity in vitro. These factors have been found in tissues of low growth fraction and appear to be absent or low in tissues or high growth fraction such as tumor, regenerating liver and embryonic tissues. The expression of intracellular ribonucleotide reductase activity is therefore controlled at various levels and by various factors and the prevailing mode of regulation may vary throughout the cell cycle transverse and also in the various types of cells.