Replicative DNA polymerases (Pol α, Pol δ, Pol ε)

Replicative DNA polymerases are a specialized group of enzymes, primarily including DNA polymerase alpha (Pol α), delta (Pol δ), and epsilon (Pol ε), that are essential for the duplication of the nuclear genome during the S-phase of the cell cycle [1, 13]. These enzymes work coordinately at the replication fork: Pol α initiates synthesis with an RNA-DNA primer, while Pol δ and Pol ε catalyze the bulk of DNA synthesis on the lagging and leading strands, respectively [9, 15]. Beyond replication, these polymerases play vital roles in various DNA repair pathways, such as nucleotide excision repair and mismatch repair, ensuring high-fidelity transmission of genetic information [1, 5]. In the context of disease, the dysregulation or overactivity of these polymerases is a hallmark of rapidly proliferating cancer cells, making them prime targets for chemotherapy [2, 8]. Therapeutic agents targeting these enzymes include nucleoside analogs like cytarabine and gemcitabine, which are incorporated into the nascent DNA strand and cause chain termination or replication stress [2, 12]. While effective in killing tumor cells, these drugs also affect normal dividing cells, leading to common clinical side effects such as myelosuppression and gastrointestinal distress [2, 4]. Understanding the specific roles and structural differences of these polymerases continues to drive the development of more selective inhibitors aimed at overcoming drug resistance in oncology [5, 6].

Other names

Nuclear DNA polymerasesDNA-directed DNA polymerasesEukaryotic replicative DNA polymerasesDNA polymerase alpha, delta, and epsilon

Nucleoside analogs act as antimetabolites that are phosphorylated into active triphosphate forms, which then compete with natural dNTPs for incorporation into DNA by replicative polymerases, leading to DNA chain termination, replication fork stalling, and induction of apoptosis [2, 12].