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

Ribonucleoside-diphosphate reductase (RNR) and DNA polymerase are essential enzymes that work in tandem to facilitate DNA synthesis and repair (NCBI: PMC3154436). RNR is responsible for the rate-limiting step of converting ribonucleoside diphosphates (NDPs) into deoxyribonucleoside diphosphates (dNDPs), thereby maintaining the balanced pool of deoxyribonucleotides (dNTPs) required for genomic integrity (UniProt: P23921). DNA polymerase then utilizes these dNTPs to assemble DNA strands during replication and repair processes (Nature Scitable: DNA Polymerase). This pathway is a major target for antimetabolite chemotherapy; drugs like gemcitabine and clofarabine inhibit RNR to deplete dNTP levels and are also incorporated into DNA by DNA polymerase, leading to chain termination and cell death (DrugBank: DB00441). Consequently, these targets are pivotal in the treatment of various cancers, including leukemias and solid tumors (NCI: Antimetabolites). The dual inhibition of these enzymes is a common strategy to overcome resistance and enhance the efficacy of nucleoside-based therapies (PubMed: 11861271).

Other names

Ribonucleotide reductaseDNA-directed DNA polymeraseRNRDNA polRRM1/RRM2 complexDNA polymerase alpha/delta/epsilon

Nucleoside analogs act as prodrugs that are phosphorylated to active forms; the diphosphate form typically inhibits ribonucleoside-diphosphate reductase, while the triphosphate form competes with natural dNTPs for incorporation into DNA by DNA polymerase, leading to DNA strand termination or stalling of the replication fork (DrugBank: DB00441).