Fig. 7

Schematic model of the role of ATF2 in DDR upon 5-FU exposure depending on p53 mutation status. DNA-damaging reagents such as 5-FU induce the DDR pathway. ATR, as a sensor of DNA damage, phosphorylates its downstream target Chk1 upon activation, allowing DNA repair. After 5-FU treatment, ATF2 binds to ATR to suppress the p-ATR/Chk1 protein kinase cascade, triggering apoptosis. Upon ATF2-KO, the interaction of p-ATR/Chk1 is no longer blocked, leading to apoptosis resistance. p53-mutant cells (HT29) show a p53-p-ATR-Chk1-ATF2 complex upon 5-FU exposure. Whereas ATF2 is still in complex with p-ATR, it is released from the complex with mutant p53. Thus, ATF2 cannot inhibitory interact with the p-ATR-Chk1 complex. The resulting changes in complex conformation induce drug resistance accompanied by high p-Chk1 levels