An intrinsic S/G2 checkpoint enforced by ATR

An additional cell cycle checkpointCell division is controlled by checkpoints that regulate the temporal order of the cell cycle phases, including the G1/S, G2/M, and metaphase/anaphase transitions. Yet there are no known control mechanisms for a fourth fundamental transition—the S/G2 transition. Saldivar et al. report a switchlike control mechanism that regulates the S/G2 transition. The checkpoint kinase ATR senses ongoing DNA replication in S phase and represses the mitotic transcriptional network, ensuring that DNA replication in S phase is completed before mitosis.Science, this issue p. 806The cell cycle is strictly ordered to ensure faithful genome duplication and chromosome segregation. Control mechanisms establish this order by dictating when a cell transitions from one phase to the next. Much is known about the control of the G1/S, G2/M, and metaphase/anaphase transitions, but thus far, no control mechanism has been identified for the S/G2 transition. Here we show that cells transactivate the mitotic gene network as they exit the S phase through a CDK1 (cyclin-dependent kinase 1)–directed FOXM1 phosphorylation switch. During normal DNA replication, the checkpoint kinase ATR (ataxia-telangiectasia and Rad3-related) is activated by ETAA1 to block this switch until the S phase ends. ATR inhibition prematurely activates FOXM1, deregulating the S/G2 transition and leading to early mitosis, underreplicated DNA, and DNA damage. Thus, ATR couples DNA replication with mitosis and preserves genome integrity by enforcing an S/G2 checkpoint.