DNA polymerase and replication machinery (Replisome) (DNA Pol/Replisome)

DNA polymerase and the replication machinery, collectively known as the replisome, are the multi-protein systems responsible for the high-fidelity duplication of the genome [StatPearls: NBK534815]. This complex includes various DNA-directed DNA polymerases (such as Pol α, δ, and ε), helicases, and processivity factors like the Proliferating Cell Nuclear Antigen (PCNA) [UniProt: P12004]. Because rapid cell division is a hallmark of both malignancy and infectious pathogens, this machinery is a primary target for chemotherapy and antiviral therapy [PubMed: 28251595]. Drugs targeting this system, such as nucleoside analogs, typically act as antimetabolites that cause DNA chain termination or competitively inhibit the polymerase active site [PubChem: CID 60750]. However, the essential nature of DNA replication in healthy tissues leads to common safety concerns, including myelosuppression and gastrointestinal toxicity [NIH: Cancer Chemotherapy]. Additionally, mutations in the proofreading domains of polymerases (e.g., POLE) serve as important biomarkers for predicting high tumor mutational burden and favorable responses to immunotherapy [PubMed: 31043484].

Other names

ReplisomeDNA replication complexDNA synthesis machineryDNA-directed DNA polymerase complex

Inhibition of DNA synthesis via competitive binding with natural deoxynucleotides, DNA chain termination, or direct enzymatic blockade of the polymerase active site [PubMed: 28251595, StatPearls: NBK542180].