DNA polymerase delta (Pol delta) and DNA polymerase epsilon (Pol epsilon) (Pol delta/epsilon)

DNA polymerase delta (Pol delta) and DNA polymerase epsilon (Pol epsilon) are the primary high-fidelity enzymes responsible for eukaryotic genomic DNA replication (Burgers & Kunkel, 2017, PMID: 28301277). Pol epsilon is generally responsible for leading-strand synthesis, while Pol delta primarily synthesizes the lagging strand and completes Okazaki fragment processing (UniProtKB - P28340; UniProtKB - Q07864). Both enzymes possess intrinsic 3' to 5' exonuclease activity, which provides a critical proofreading function to maintain genomic stability (Heitzer & Tomlinson, 2014, PMID: 24501277). Mutations in the proofreading domains of these polymerases, particularly in the POLD1 and POLE genes, are associated with ultra-mutated phenotypes in various cancers, such as colorectal and endometrial carcinomas (Church et al., 2013, PMID: 23263490). Therapeutically, these polymerases are the targets of several antimetabolite drugs, including nucleoside analogs like cytarabine and gemcitabine, which inhibit DNA synthesis and induce apoptosis in rapidly dividing cells (PubChem CID 6253; PubChem CID 60750). Understanding the status of these enzymes is increasingly important for precision oncology, as polymerase-mutated tumors often exhibit high mutational burdens and may be particularly sensitive to immune checkpoint inhibitors (Le et al., 2015, PMID: 26028255).

Other names

POLDPOLEDNA polymerase delta complexDNA polymerase epsilon complexReplicative DNA polymerasesPOLD1POLE1

Inhibition of DNA synthesis through competitive binding with natural deoxynucleotides and/or incorporation into the nascent DNA strand leading to premature chain termination.