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

The ribonucleoside-diphosphate reductase (RNR) and DNA polymerase machinery represent a critical enzymatic axis for DNA synthesis and repair. RNR is responsible for the rate-limiting step of converting ribonucleoside diphosphates into deoxyribonucleoside diphosphates, which are the essential building blocks for DNA [1, 2]. DNA polymerases then utilize these deoxyribonucleotides to synthesize new DNA strands during replication and repair processes [3]. Many antimetabolite chemotherapeutic agents, such as gemcitabine and clofarabine, exert their effects by targeting both components of this machinery [4]. By inhibiting RNR, these drugs deplete the intracellular pools of dNTPs, which enhances the incorporation of the drug's active triphosphate form into DNA by DNA polymerase, ultimately leading to chain termination and apoptosis [5]. This dual-targeting strategy is particularly effective in treating various hematological malignancies and solid tumors [6]. References: [1] Nordlund & Reichard (2006) Annu Rev Biochem; [2] Kolberg et al. (2004) Biochim Biophys Acta; [3] Hübscher et al. (2002) DNA Polymerases; [4] Galmarini et al. (2002) Lancet Oncol; [5] Cerqueira et al. (2007) Curr Med Chem; [6] StatPearls: Gemcitabine.

Other names

Ribonucleotide reductase and DNA polymeraseDNA replication machineryRNR and DNA polymerase complex

Inhibition of ribonucleotide diphosphate reductase leads to depletion of deoxyribonucleotide pools, while inhibition of DNA polymerase prevents the assembly of DNA strands, collectively halting DNA synthesis and repair.