FIGURE 19-30 Overview of DNA damage checkpoint controls in the cell cycle. During G₁, the p53-p21 pathway inhibits G₁ CDKs. During ongoing DNA replication and in response to replication stress (slow DNA replication fork movement or DNA replication fork collapse), the ATR-Chk1 protein kinase cascade phosphorylates and inactivates Cdc25C, thereby preventing the activation of mitotic CDKs and inhibiting entry into mitosis. In response to DNA damage, the ATM or ATR protein kinases (ATM/R) inhibit Cdc25 via the Chk1/2 protein kinases. They also activate p53, which induces production of the CKI p21. During G₁, the DNA damage checkpoint pathway inhibits Cdc25A, inhibiting G₁/S phase CDKs and S phase CDKs, and thereby blocking entry into or passage through S phase. During G₂, ATM/R and Chk1/2 inhibit Cdc25C. The p53-p21 pathway is also activated. Red symbols indicate pathways that inhibit progression through the cell cycle.