DNA replication determines timing of mitosis by restricting CDK1 and PLK1 activation

Lemmens, Bennie, Hegarat, Nadia, Akopyan, Karen, Sala-Gaston, Joan, Bartek, Jiri, Hochegger, Helfrid and Lindqvist, Arne (2018) DNA replication determines timing of mitosis by restricting CDK1 and PLK1 activation. Molecular Cell, 71 (1). 117-128.e3. ISSN 1097-2765

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Abstract

To maintain genome stability, cells need to replicate their DNA before dividing. The kinases CDK1 and PLK1 drive mitotic entry and become active when bulk DNA synthesis is completed at the S/G2 transition. Here, we have tested the hypothesis that DNA replication controls activation of mitotic kinases. Using an optimized double-degron system, we find that human cells unable to initiate DNA replication in S-phase promptly activate CDK1 and PLK1 and prematurely enter mitosis. In the presence of DNA replication, inhibition of CHK1 and p38 leads to premature activation of CDK1 and PLK1. While CDK2 activity promotes DNA replication, activation of CDK1 in S-phase induces severe replication stress. We propose that mitotic kinase activation is governed by a CDK2- and DNA replication-dependent feed-forward loop that ensures timely cell division while preserving genome stability. DNA replication thus functions as a break that coordinates cell cycle activities and determines cell cycle duration.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Subjects: Q Science
Q Science > Q Science (General)
Depositing User: Sarah Frances
Date Deposited: 13 Dec 2018 14:34
Last Modified: 13 Dec 2018 14:36
URI: http://sro.sussex.ac.uk/id/eprint/80760

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Project NameSussex Project NumberFunderFunder Ref
Exploiting chemical genetics to investigate the control of microtubule dynamics by mitotic kinasesG0900CANCER RESEARCH UKC28206/A14499
Systems-level characterization of mammalian cell cycle transitions (sLoLa Oxford lead)G1488BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCILBB/MM00354X/1