Ribonucleotide reductase and DNA polymerases (RNR and DNA Pol)

Ribonucleotide reductase (RNR) and DNA polymerases are essential enzymes that work in tandem to ensure accurate and timely DNA synthesis and repair. RNR is responsible for the rate-limiting step of de novo deoxyribonucleotide (dNTP) production by catalyzing the reduction of ribonucleoside diphosphates into deoxyribonucleoside diphosphates [1][2]. DNA polymerases then utilize these dNTPs to synthesize new DNA strands during replication and fill gaps during DNA repair processes [3]. In oncology, these enzymes are frequently targeted together by nucleoside analogs such as gemcitabine and fludarabine [4]. These drugs often act as dual-action agents: their metabolites inhibit RNR to deplete natural nucleotide pools while simultaneously competing with those pools for incorporation into DNA by DNA polymerases, leading to chain termination and apoptosis [4][5]. Because of their central role in cell proliferation, these targets are critical in treating various hematological malignancies and solid tumors, though their inhibition often results in significant side effects like myelosuppression [6].

Other names

RNRRibonucleoside-diphosphate reductaseDNA-directed DNA polymeraseDNA PolNucleotide metabolism enzymes

Inhibition of ribonucleotide reductase prevents the conversion of ribonucleotides to deoxyribonucleotides, depleting the dNTP pool; subsequent inhibition of DNA polymerases by nucleoside analogs leads to DNA chain termination or stalled replication forks.