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An intrinsic S/G2 checkpoint enforced by ATR

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Science  24 Aug 2018:
Vol. 361, Issue 6404, pp. 806-810
DOI: 10.1126/science.aap9346

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An additional cell cycle checkpoint

Cell 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. 806

Abstract

The 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.

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