DNA, DNA polymerase, and ribonucleotide reductase

The combination of DNA, DNA polymerase, and ribonucleotide reductase (RNR) represents the fundamental molecular axis for genetic inheritance and cellular proliferation [1]. Ribonucleotide reductase is the primary enzyme responsible for the de novo synthesis of deoxyribonucleotides (dNTPs) by reducing ribonucleotides, thereby controlling the rate-limiting step of DNA precursor production [2]. DNA polymerases subsequently utilize these dNTPs to synthesize new DNA strands during the S-phase of the cell cycle and to perform essential DNA repair following damage [3]. This pathway is a major focal point for oncology therapeutics, particularly antimetabolites like gemcitabine, cladribine, and cytarabine [4]. These drugs often exert a synergistic effect by inhibiting RNR to starve the cell of nucleotides while simultaneously being incorporated into the DNA template by DNA polymerases, leading to replication fork collapse and programmed cell death [4][5]. Due to the high replication rate of malignant cells, this pathway is highly sensitive to inhibition, though its essential role in hematopoiesis leads to common clinical side effects such as neutropenia and anemia [5].

Other names

DNA replication machinerydNTP synthesis and polymerization pathwayAntimetabolite target complex

Inhibition of ribonucleotide reductase (RNR) to deplete deoxyribonucleotide pools, competitive inhibition of DNA polymerases, and direct incorporation into DNA strands leading to chain termination and induction of apoptosis.