Human DNA polymerases (DNA Pol)

Human DNA polymerases are a group of essential enzymes responsible for the synthesis and repair of DNA in both the nucleus and mitochondria. The nuclear polymerases, including families A, B, X, and Y, perform distinct roles such as bulk genomic replication (Pol alpha, delta, epsilon) and specialized DNA repair (Pol beta, lambda, mu) [StatPearls, 2023]. The mitochondrial DNA polymerase, Pol gamma, is the sole enzyme responsible for the replication and maintenance of the mitochondrial genome [UniProt P54098]. These enzymes are critical therapeutic targets; for example, many nucleoside analog chemotherapies like Cytarabine and Gemcitabine target nuclear polymerases to inhibit cancer cell proliferation [PubMed, 2021]. However, they are also significant sites of off-target drug toxicity. Specifically, the inhibition of Pol gamma by certain antiviral nucleoside reverse transcriptase inhibitors (NRTIs) can lead to mitochondrial DNA depletion, resulting in severe clinical conditions such as lactic acidosis, myopathy, and lipodystrophy [NIH, 2022]. Furthermore, mutations in polymerase genes like POLE and POLD1 serve as important biomarkers for hypermutation status and immunotherapy sensitivity in various cancers [PubMed, 2019].

Other names

DNA-directed DNA polymeraseNuclear DNA polymerasesMitochondrial DNA polymeraseDNA polymerase gamma (POLG)DNA polymerase alpha (POLA)DNA polymerase beta (POLB)DNA polymerase delta (POLD)DNA polymerase epsilon (POLE)

Inhibition of DNA synthesis through competitive binding with deoxyribonucleotide triphosphates (dNTPs) or by acting as chain terminators after incorporation into the nascent DNA strand [StatPearls, 2023].