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Mol Cell. 2018 Jul 5;71(1):117-128.e3. doi: 10.1016/j.molcel.2018.05.026. Epub 2018 Jun 28.

DNA Replication Determines Timing of Mitosis by Restricting CDK1 and PLK1 Activation.

Author information

1
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet and Science for Life Laboratory, Stockholm, Sweden.
2
Genome Damage and Stability Centre, University of Sussex, Brighton, UK.
3
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
4
Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet and Science for Life Laboratory, Stockholm, Sweden; Danish Cancer Society Research Center, Copenhagen, Denmark.
5
Genome Damage and Stability Centre, University of Sussex, Brighton, UK. Electronic address: h.hochegger@sussex.ac.uk.
6
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. Electronic address: arne.lindqvist@ki.se.

Abstract

To maintain genome stability, cells need to replicate their DNA before dividing. Upon completion of bulk DNA synthesis, the mitotic kinases CDK1 and PLK1 become active and drive entry into mitosis. Here, we have tested the hypothesis that DNA replication determines the timing of mitotic kinase activation. Using an optimized double-degron system, together with kinase inhibitors to enforce tight inhibition of key proteins, we find that human cells unable to initiate DNA replication prematurely enter mitosis. Preventing DNA replication licensing and/or firing causes prompt activation of CDK1 and PLK1 in S phase. In the presence of DNA replication, inhibition of CHK1 and p38 leads to premature activation of mitotic kinases, which induces severe replication stress. Our results demonstrate that, rather than merely a cell cycle output, DNA replication is an integral signaling component that restricts activation of mitotic kinases. DNA replication thus functions as a brake that determines cell cycle duration.

KEYWORDS:

CDK1; DNA replication; G2 phase; PLK1; S phase; cell cycle; mitosis; replication checkpoint

PMID:
30008317
PMCID:
PMC6039720
DOI:
10.1016/j.molcel.2018.05.026
[Indexed for MEDLINE]
Free PMC Article

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