Ribonucleotide reductase catalytic subunit M1 and DNA polymerase (RRM1/DNA Pol)

Ribonucleotide reductase catalytic subunit M1 (RRM1) and DNA polymerase are critical enzymes in DNA synthesis and repair that are often targeted simultaneously by nucleoside analog chemotherapeutics (https://www.uniprot.org/uniprotkb/P23921/entry). RRM1 is the large subunit of ribonucleotide reductase, which catalyzes the rate-limiting step in the production of deoxyribonucleotides (dNTPs) by reducing ribonucleoside diphosphates (https://pubmed.ncbi.nlm.nih.gov/17305393/). DNA polymerases are a family of enzymes responsible for the polymerization of dNTPs into a DNA strand during replication and repair (https://www.ncbi.nlm.nih.gov/books/NBK9940/). In oncology, drugs like gemcitabine act as prodrugs; their diphosphate metabolite inhibits RRM1 to reduce the concentration of natural dNTPs, while their triphosphate metabolite is incorporated into DNA by DNA polymerase (https://pubmed.ncbi.nlm.nih.gov/7743117/). This dual action results in "masked chain termination," where the drug is incorporated and then followed by one additional natural nucleotide, preventing DNA repair enzymes from removing the analog and ultimately leading to apoptosis (https://pubmed.ncbi.nlm.nih.gov/11106091/). High expression of RRM1 is a known biomarker for resistance to gemcitabine-based therapies in cancers such as non-small cell lung cancer and pancreatic adenocarcinoma (https://pubmed.ncbi.nlm.nih.gov/15150105/).

Other names

R1RR1Ribonucleoside-diphosphate reductase large subunitDNA nucleotidyltransferaseDNA-directed DNA polymerase

Inhibition of RRM1 leads to the depletion of intracellular deoxyribonucleotide pools, which reduces competition for DNA polymerase and facilitates the incorporation of nucleoside analog triphosphates into DNA, resulting in masked chain termination and apoptosis.