Dysregulation of dNTP pools in cancer and its strategic regulation

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Ribonucleotide reductase (RR) is a rate-limiting enzyme for DNA synthesis as it catalyses the conversion of ribonucleoside diphosphates to their corresponding deoxyribonucleotides. p53R2, which encodes a small subunit of RR, was recently identified to be a new p53-target gene, and was shown to play a pivotal role in dNTP supply for DNA repair. In most cancers, in which p53 is inactivated, the expression of p53R2 is dysregulated, implying attenuation of dNTP pools for DNA repair and the resulting accumulation of spontaneous mutations in cancer cells.

Since RR is essential for cell division and cell growth, the enzyme has been a target for anti-cancer drug. Hydroxyurea is one of the inhibitors for RR, and it is used as an anticancer-drug for the patients with hematopoietic cancers. Inhibition of RR induces depletion of intracellular dNTP pools, leading to cell-cycle arrest and apoptosis. To discover new inhibitors for RR, the mechanism of the regulation of dNTP pools is under investigation.