Figure 1.

A Schematic Diagram of the S-Phase DNA Damage Checkpoint

DNA damage that block polymerases during S-phase activates the ATR/Mec1/Rad3 checkpoint kinase, which activates the S-phase DNA damage checkpoint. ATR/Mec1/Rad3 is activated locally at sites of DNA damage, therefore its targets are local to sites of damage. However, one of its major targets is activation of the S-phase checkpoint effector kinase Chk1/Rad53/Cds1, which is freely diffusible and triggers a global checkpoint response. A subset of Chk1/Rad53/Cds1 targets, those that constitute the intra-S-phase branch of the checkpoint, regulate replication dynamics by inhibiting origin firing and slowing fork progression. Although the regulation of origin firing is an intrinsically global effect, it is unclear if forks are regulated globally, with all forks being slowed, or locally, with slowing reflecting checkpoint-dependent pausing of forks that encounter damage. The many protein targets of these kinases have been reported recently [15,63–65].