ATR inhibition selectively sensitizes G(1) checkpoint-deficient cells to lethal premature chromatin condensation

Premature chromatin condensation (PCC) is a hallmark of mammalian cells tha t begin mitosis before completing DNA replication. This lethal event is pre vented by a highly conserved checkpoint involving an unknown, caffeine-sens itive mediator. Here, we have examined the possible involvement of the caff eine-sensitive ATM and ATR protein kinases in this check point. We show tha t caffeine's ability to inhibit ATR (but not ATM) causes PCC, that ATR (but not ATM) prevents PCC, and that ATR prevents PCC via Chk-1 regulation. Mor eover, mimicking cancer cell phenotypes by disrupting normal Gt checkpoints sensitizes cells to PCC by ATR inhibition plus tow-dose DNA damage. Notabl y, loss of p53 function potently sensitizes cells to PCC caused by ATR inhi bition by a small molecule. We present a molecular model for how ATR preven ts PCC and suggest that ATR represents an attractive therapeutic target for selectively killing cancer cells by premature chromatin condensation.