Fig 2: The synthetic lethal interaction between ATR and the p53 pathway in cells exposed to topoisomerase II inhibitor etoposide.Inhibition of ATR leads to accumulation of DSBs from collapsed stalled replication forks or by the replication stress triggered by etoposide inhibition of Top2. In functional WT p53 cells (A), with intact cell cycle checkpoints, other compensatory mechanisms reduce proliferation and promote repair. This contrasts with p53-deficient cells (B) that have lost G1 checkpoint control and where the initiation of DNA replication continues along with an accumulation of DNA damage. Since p53 deficient cells rely on the ATR/Chk1 pathway S/G2 checkpoints for repairing DNA damage, the ATR inhibition (C) results in selective killing of cancer cells due to the accumulation of etoposide-induced Top2cc DNA lesions and higher levels of unrepaired damage. This would lead to increased cell death, possibly due to mitotic catastrophe or as a consequence of loss of G2/M arrest. Normal cells with a functional p53 and G1 checkpoint would be less affected.