Regulation of ribonucleotide reductase activity in mammalian cells

Abstract

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.

Multi-attenuated herpes simplex virus-1 mutant G207 exerts cytotoxicity against epithelial ovarian cancer but not normal mesothelium and is suitable for intraperitoneal oncolytic therapy

“…In fact, RR is implicated in the control of DNA synthesis. 37 The loss of RR was anticipated to further abrogate the ability of HSV ICP34.5 Ϫ virus mutants to replicate in normal quiescent cells, 38 which lack expression of endogenous RR. 37 As a result, the tumor specificity profile of RR Ϫ viruses would be significantly enhanced.…”

“…37 The loss of RR was anticipated to further abrogate the ability of HSV ICP34.5 Ϫ virus mutants to replicate in normal quiescent cells, 38 which lack expression of endogenous RR. 37 As a result, the tumor specificity profile of RR Ϫ viruses would be significantly enhanced. 15 Fulfilling the expectations, HSV-G207 has been shown to exhibit minimal toxicity in the experimental treatment of various CNS and extra-CNS tumors.…”

“…38 Its cytoplasmic levels are regulated during the cell cycle in mammalian cells: the R1 subunit is absent in quiescent normal cells in G 0 phase and is newly acquired during transition to G 1 phase, 40 whereas the R2 subunit is up-regulated in S phase. 37 During the cell cycle, the enzyme levels markedly increase during the S phase. 37 As a result, levels of both subunits are abundant in normal proliferating cells but absent in quiescent diploid cells.…”

“…37 During the cell cycle, the enzyme levels markedly increase during the S phase. 37 As a result, levels of both subunits are abundant in normal proliferating cells but absent in quiescent diploid cells. In both normal and malignant cells, levels of RR were found to correlate with markers of proliferation such as Ki-67 and proliferating cell nuclear Ag.…”

Ribonucleotide reductase subunits M1 and M2 mRNA expression levels and clinical outcome of lung adenocarcinoma patients treated with docetaxel/gemcitabine

“…Ribonucleotide reductase (RR) is an enzyme of central importance in DNA synthesis (Cory and Sato, 1983). Ribonucleotide reductase catalyses the conversion of ribonucleotide 5 0 -diphosphates to their 2 0 -deoxynucleotide forms, a rate-limiting step in the production of 2 0 -deoxyribonucleoside 5 0 -triphosphates (dNTP) required for DNA synthesis (Cory, 1997).…”