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

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Version 2 2023-06-12, 08:55
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journal contribution
posted on 2023-06-12, 08:55 authored by Bennie Lemmens, Nadia Hegarat, Karen Akopyan, Joan Sala-Gaston, Jiri Bartek, Helfrid HocheggerHelfrid Hochegger, Arne Lindqvist
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.

Funding

Exploiting chemical genetics to investigate the control of microtubule dynamics by mitotic kinases; G0900; CANCER RESEARCH UK; C28206/A14499

Systems-level characterization of mammalian cell cycle transitions (sLoLa Oxford lead); G1488; BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCIL; BB/MM00354X/1

History

Publication status

  • Published

File Version

  • Published version

Journal

Molecular Cell

ISSN

1097-2765

Publisher

Elsevier

Issue

1

Volume

71

Page range

117-128.e3

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-12-13

First Open Access (FOA) Date

2018-12-13

First Compliant Deposit (FCD) Date

2018-12-13

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