Ribonucleotide reductase regulatory subunit M2 and DNA polymerase (RRM2/DNA Pol)

Ribonucleotide reductase regulatory subunit M2 (RRM2) and DNA polymerase are distinct but functionally linked enzymes essential for genomic integrity and cellular proliferation. RRM2 is a key component of the ribonucleotide reductase complex, which catalyzes the rate-limiting step in the production of deoxyribonucleotides (dNTPs) required for DNA synthesis (UniProt: P31350). DNA polymerases are the enzymes responsible for the actual polymerization of these dNTPs into DNA strands during replication and repair processes (UniProt: P09884). This dual-target profile is a hallmark of several potent nucleoside analog chemotherapies, such as clofarabine and gemcitabine. These drugs inhibit RRM2 to deplete natural dNTP pools, which enhances the likelihood of the drug's active triphosphate metabolite being incorporated into DNA by DNA polymerase, ultimately causing chain termination and cell death (PubMed: 12750183, PubMed: 10486037). Consequently, this target axis is primarily exploited in oncology for the treatment of various leukemias and solid tumors. However, because these enzymes are vital for all dividing cells, therapeutic intervention is often limited by significant systemic toxicities, most notably bone marrow suppression.

Other names

RNR M2Ribonucleoside-diphosphate reductase subunit M2DNA-directed DNA polymeraseRRM2/POL

Dual inhibition where RRM2 inhibition depletes intracellular dNTP pools, which subsequently facilitates the incorporation of nucleoside analog triphosphates into DNA by DNA polymerase, leading to DNA chain termination and apoptosis.