DNA replication complex (Replisome) (Replisome)

The DNA replication complex, or replisome, is a highly coordinated multi-protein assembly that executes the duplication of a cell's genetic material during the S phase of the cell cycle (Wikipedia, 2024). It consists of core enzymes such as DNA polymerases (α, δ, and ε), the CMG helicase complex (Cdc45-MCM-GINS), and processivity factors like the proliferating cell nuclear antigen (PCNA) (NIH, 2019). This complex is a cornerstone of therapeutic intervention in oncology, as cancer cells rely on its high activity for rapid proliferation (MDPI, 2022). Drugs like gemcitabine and irinotecan target its components to induce replication stress, stall replication forks, and ultimately trigger apoptosis (NIH, 2019). Additionally, the replication machinery of pathogens is a key target for anti-infectives, such as fluoroquinolones that inhibit bacterial topoisomerases and nucleoside analogs that block viral DNA polymerases (PubMed, 2013). Therapeutic challenges include significant off-target toxicity to healthy dividing cells, leading to side effects like myelosuppression and mucositis (NIH, 2019). The development of drug resistance through mutations in replication factors or upregulation of bypass polymerases remains a major hurdle in clinical efficacy (NIH, 2019). Biomarkers like PCNA and MCM proteins are frequently used to assess the proliferative state of tumors and monitor treatment response (NIH, 2022).

Other names

ReplisomeDNA replication machineryDNA synthesomeDNA replication apparatusDNA replication fork complex

Inhibition of DNA polymerase activity, induction of replication fork stalling, trapping of topoisomerase-DNA cleavage complexes, and depletion of deoxyribonucleotide pools.