Ribonucleoside-diphosphate reductase (RNR) and DNA-directed DNA polymerase (DNA Pol) (RNR and DNA Pol)

Ribonucleoside-diphosphate reductase (RNR) and DNA-directed DNA polymerases are essential enzymes for DNA synthesis and repair, making them critical targets in oncology [1]. RNR is responsible for the de novo synthesis of deoxyribonucleotides (dNTPs) by reducing ribonucleoside diphosphates, a rate-limiting step in DNA production [2]. DNA polymerases utilize these dNTPs to replicate the genome during the S phase of the cell cycle [3]. Gemcitabine, a pyrimidine nucleoside analog, acts as a prodrug that is intracellularly activated to its diphosphate (dFdCDP) and triphosphate (dFdCTP) forms [1]. dFdCDP potently inhibits RNR, leading to a depletion of the intracellular dCTP pool, which facilitates the incorporation of dFdCTP into DNA by DNA polymerases [4]. Once incorporated, gemcitabine induces "masked chain termination," where the addition of one extra nucleotide prevents DNA repair mechanisms from removing the analog, ultimately leading to replication fork collapse and apoptosis [2, 4].

Other names

Ribonucleotide reductaseDNA polymeraseRNA polymeraseRibonucleoside-diphosphate reductaseDNA-directed DNA polymeraseRRM1RRM2DNA Pol alphaDNA Pol deltaDNA Pol epsilon

Gemcitabine diphosphate inhibits ribonucleotide reductase to deplete dNTP pools, while gemcitabine triphosphate is incorporated into DNA by DNA polymerase, causing masked chain termination.