Figure 4.

Cell cycle checkpoints elicited by UV-induced ATR activation. G₁-S checkpoint: Following UV-induced DNA damage in G₁ phase, activated ATR phosphorylates p53 at Ser15 and CHK1 at Ser345. Phospho-CHK1 inactivates CDC25A, preventing dephosphorylation of CDK2 and inducing G₁ arrest. The p53-p21 pathway also inhibits CDK2. Intra-S checkpoint: UV activates the ATR-CHK1 pathway in S phase, decreasing the function of CDK. DNA replication origin firing requires phosphorylation of Treslin by CDK, and thus it is plausible that replication stress prevents origin firing via inhibiting Treslin phosphorylation. S-G₂ checkpoint: ATR senses ongoing DNA replication during unperturbed S phase, inhibiting CDK1 activity and preventing cell cycle progression to G₂ phase. When DNA replication is completed, ATR activity is diminished, allowing CDK1 to phosphorylate FOXM1 for S-G₂ transition. G₂-M checkpoint: UV-induced ATR-CHK1 activation inhibits CDC25C and CDK1 activities, preventing G₂-M transition. WEE1 phosphorylates and inhibits CDK1, also inducing G₂ arrest.