DNA polymerase delta and DNA polymerase epsilon (Pol δ and Pol ε)

DNA polymerases delta (Pol δ) and epsilon (Pol ε) are the primary replicative enzymes in eukaryotic cells, responsible for the high-fidelity synthesis of the lagging and leading DNA strands, respectively (Wikipedia, 2024; NIH, 2011). These enzymes, often functioning in complex with DNA and accessory proteins like PCNA, are essential for chromosomal duplication and various DNA repair pathways, including mismatch repair (MMR) and base excision repair (BER) (Frontiers, 2010; NIH, 2022). In oncology, they are significant both as therapeutic targets and as biomarkers; nucleoside analogs like cytarabine and gemcitabine inhibit these polymerases to disrupt the rapid proliferation of cancer cells (NIH, 2008; Frontiers, 2010). Furthermore, somatic or germline mutations in the proofreading domains of POLE and POLD1 lead to "ultramutated" tumor phenotypes, which serve as critical biomarkers for predicting favorable responses to immune checkpoint inhibitors (NIH, 2019; ASCO, 2022). Targeting these polymerases or exploiting their mutational status represents a key strategy in precision oncology and the treatment of hematologic and solid malignancies (NIH, 2022; ecancer, 2015).

Other names

POLD1POLEDNA-directed DNA polymerase deltaDNA-directed DNA polymerase epsilonReplicative DNA polymerasesDNA polymerase delta/epsilon-DNA complex

Inhibition of DNA synthesis through competition with natural deoxynucleoside triphosphates (dNTPs), induction of DNA chain termination, or stalling of the polymerase at DNA lesions (Frontiers, 2010; NIH, 2008).