An intrinsic S/G2 checkpoint enforced by ATR

  • Science. 2018 Aug 24;361(6404):806-810. doi: 10.1126/science.aap9346.
Joshua C Saldivar  1 ,  Stephan Hamperl  1 ,  Michael J Bocek  1 ,  Mingyu Chung  1 ,  Thomas E Bass  2 ,  Fernanda Cisneros-Soberanis  3  4 ,  Kumiko Samejima  3 ,  Linfeng Xie  5 ,  James R Paulson  5 ,  William C Earnshaw  3 ,  David Cortez  2 ,  Tobias Meyer  1 ,  Karlene A Cimprich  6
Affiliations
  • 1. Department of Chemical and Systems Biology, Stanford University School of Medicine, 318 Campus Drive, Stanford, CA 94305-5441, USA.
  • 2. Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, Nashville, TN 37232, USA.
  • 3. Wellcome Centre for Cell Biology, University of Edinburgh, King's Buildings, Max Born Crescent, Edinburgh EH9 3BF, Scotland, UK.
  • 4. Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas-Universidad Nacional Autónoma de México; Insituto Nacional de Cancerología, México City 14080, Mexico.
  • 5. Department of Chemistry, University of Wisconsin-Oshkosh, 800 Algoma Boulevard, Oshkosh, WI 54901, USA.
  • 6. Department of Chemical and Systems Biology, Stanford University School of Medicine, 318 Campus Drive, Stanford, CA 94305-5441, USA. [email protected].
PMID: 30139873 DOI: 10.1126/science.aap9346
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.