DNA replication machinery (Replisome) (Replisome)

The DNA replication machinery, or replisome, is a complex multi-protein system that executes the duplication of the cellular genome during the S-phase of the cell cycle (Alberts et al., 2014). It consists of various enzymes and proteins, including DNA polymerases, the MCM helicase complex, and the PCNA sliding clamp, which work together at the replication fork to ensure high-fidelity DNA synthesis (Guilliam & Yeeles, 2020). In oncology, the replication machinery is a critical therapeutic target because cancer cells often exhibit high rates of proliferation and increased replication stress (O'Connor, 2015). Traditional chemotherapies target this machinery by inhibiting nucleotide synthesis or directly damaging DNA, while newer precision therapies target the replication stress response to induce synthetic lethality in tumors (Zeman & Cimprich, 2014). Because DNA replication is essential for all dividing cells, these treatments frequently cause side effects in healthy tissues with high turnover, such as the bone marrow and intestinal lining.

Other names

DNA replication complexReplication forkDNA synthesis machineryEukaryotic replisome

Drugs targeting the DNA replication machinery function by inhibiting DNA polymerases, depleting the pool of available deoxyribonucleotides (dNTPs), or creating physical barriers such as DNA adducts that cause replication fork stalling and subsequent collapse into double-strand breaks (Zeman & Cimprich, 2014; O'Connor, 2015). Newer agents target the replication stress response, specifically inhibiting kinases like ATR or CHK1 that are required to stabilize stalled forks, thereby forcing cells into mitotic catastrophe (O'Connor, 2015).