DNA polymerase (DNA-directed DNA polymerase) (DNA Pol)

DNA polymerase is a fundamental enzyme family responsible for the synthesis of DNA strands by catalyzing the addition of nucleotides to a primer template (UniProt P09884). In clinical oncology, these enzymes are the primary targets for the active metabolite of gemcitabine, known as gemcitabine triphosphate (dFdCTP). Gemcitabine triphosphate acts as a competitive inhibitor of deoxycytidine triphosphate (dCTP), becoming incorporated into the nascent DNA chain during the S-phase of the cell cycle (PubChem CID 60750). A distinctive feature of this interaction is "masked chain termination," where the addition of a single subsequent nucleotide prevents 3'-5' exonucleolytic proofreading from removing the gemcitabine molecule (Plunkett et al., 1995). This leads to the accumulation of DNA strand breaks, inhibition of further DNA synthesis, and the induction of apoptosis in rapidly dividing cancer cells (NIH, NCI Drug Dictionary). Consequently, this target-drug interaction is a cornerstone in the treatment of various malignancies, including pancreatic, non-small cell lung, and bladder cancers (FDA Label, Gemzar).

Other names

DNA-directed DNA polymeraseDNA polymerase alphaDNA polymerase deltaDNA polymerase epsilonPOLA1POLD1POLEGemcitabine-DNA polymerase complex

Gemcitabine triphosphate (dFdCTP) competes with deoxycytidine triphosphate (dCTP) for incorporation into the DNA strand by DNA polymerases alpha, delta, and epsilon (Plunkett et al., 1995, PubMed: 7764745). Once dFdCTP is incorporated, only one additional nucleotide can be added to the growing DNA strand, a process termed "masked chain termination" (Mini Rev Med Chem, 2010, PubMed: 20470233). This additional nucleotide prevents the 3'-5' exonuclease proofreading activity of DNA polymerase from removing the gemcitabine analog, leading to irreversible DNA damage and apoptosis (StatPearls, Gemcitabine, 2023).