An intrinsic S/G checkpoint enforced by ATR

Joshua C Saldivar, Stephan Hamperl, Michael J Bocek, Mingyu Chung, Thomas E Bass, Fernanda Cisneros-Soberanis, Kumiko Samejima, Linfeng Xie, James R Paulson, William C Earnshaw, David Cortez, Tobias Meyer, Karlene A Cimprich

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)806-810
Number of pages5
JournalScience
Volume361
Issue number6404
DOIs
Publication statusPublished - 24 Aug 2018

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