DNA Replication Stress Response Pathway

The DNA replication stress response pathway is a critical cellular mechanism activated when the process of DNA replication is perturbed. Replication stress can arise from various sources, including DNA damage, depletion of nucleotide pools, inhibition of replicative polymerases, or difficult-to-replicate DNA sequences and structures. The pathway ensures the fidelity and completion of genome duplication by coordinating cell cycle progression, transcriptional responses, apoptosis, and multiple forms of DNA repair. Replication stress response pathways are frequently dysregulated in cancer cells. This contributes to ongoing genomic instability—a hallmark of cancer—and creates vulnerabilities that can be therapeutically targeted. Inhibitors targeting key components such as ATR, CHK1, and other factors involved in the response are under investigation as potential cancer therapies because tumor cells often rely more heavily on these pathways than normal cells. Additionally, targeting the replication stress response can sensitize tumors to radiotherapy and chemotherapeutic agents that induce further replicative challenges.

Inhibition of ATR/CHK1 kinases to disrupt replication stress response and induce synthetic lethality in cancer cells