Checkpoint kinase 2-Cell division cycle 25C-Cyclin-dependent kinase 1 signaling pathway (Chk2-Cdc25C-Cdc2 pathway)

The Chk2-Cdc25C-Cdc2 cell cycle checkpoint pathway is a critical regulatory axis that governs the G2/M transition in response to DNA double-strand breaks (PubMed: 11073935). Upon sensing DNA damage, the ATM kinase activates Checkpoint Kinase 2 (Chk2), which subsequently phosphorylates the phosphatase Cdc25C on Serine 216 (UniProt: O96017, P30307). This phosphorylation leads to the sequestration of Cdc25C in the cytoplasm, preventing it from dephosphorylating and activating the Cyclin-dependent kinase 1 (Cdc2/CDK1) complex (PubMed: 9334334). Consequently, the cell remains arrested in the G2 phase, allowing time for DNA repair before entering mitosis (StatPearls: NBK541079). In many cancers, this pathway is dysregulated or exploited to survive DNA-damaging therapies (PubMed: 21782188). Therapeutic targeting of this axis, particularly through Chk2 inhibitors like Prexasertib, aims to bypass the checkpoint and force damaged cells into premature mitosis, leading to mitotic catastrophe and cell death (PubMed: 25605877).

Other names

G2/M DNA damage checkpoint pathwayATM-Chk2-Cdc25C-CDK1 axisChk2-Cdc25C-CDK1 pathwayChk2-Cdc25C-Cdc2 axis

The pathway functions by inhibiting the G2/M transition through Chk2-mediated phosphorylation and inactivation of Cdc25C, which prevents the activation of the Cdc2 (CDK1)/Cyclin B complex. Drugs targeting this pathway typically inhibit Chk2 to abrogate the G2 checkpoint, sensitizing cancer cells to DNA-damaging agents by forcing them into premature mitosis.