Journal
SCIENCE
Volume 361, Issue 6404, Pages 806-809Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aap9346
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Funding
- NIH [ES016486, CA102729, GM127026]
- Wellcome Fund [107022, 203149]
- American Cancer Society [PF-15-165-01-DMC]
- Burroughs Wellcome Fund Postdoctoral Enrichment Program
- German Research Foundation DFG [HA 6996/1-1]
- Mexican Government CONACYT fellowship
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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 G(1)/S, G(2)/M, and metaphase/anaphase transitions, but thus far, no control mechanism has been identified for the S/G(2) 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/G(2) 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/G(2) checkpoint.
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