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

Lemmens, Bennie B. L. G.; Hégarat, Nadia; Akopyan, Karen; Sala-Gaston, Joan; Bártek, Jiří; Hochegger, Helfrid; Lindqvist, Arne

doi:10.1016/j.molcel.2018.05.026

Cited by 107 publications

(141 citation statements)

References 60 publications

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“…Upon completion of DNA synthesis, this inherent S/G2 checkpoint is relieved and Cdk1 phosphorylates G2‐specific transcription factors including FOXM1 and B‐MYB, resulting in the synthesis of proteins involved in the G2/M transition including cyclin B. Likewise, results from the Lindqvist lab demonstrate a distinctive increase in Cdk1 and Plk1 activity coinciding with the completion of DNA replication and demonstrate that DNA replication generates a direct brake on mitotic entry. They establish conditions where origin licensing and firing is suppressed and find that this results in an accelerated mitotic entry in the absence of S phase.…”

Section: Organising Mitosis: Open Questions In the Mitotic Entry Fieldmentioning

confidence: 94%

Triggering mitosis

Crncec

Hochegger

2019

FEBS Letters

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Entry into mitosis is triggered by the activation of cyclin‐dependent kinase 1 (Cdk1). This simple reaction rapidly and irreversibly sets the cell up for division. Even though the core step in triggering mitosis is so simple, the regulation of this cellular switch is highly complex, involving a large number of interconnected signalling cascades. We do have a detailed knowledge of most of the components of this network, but only a poor understanding of how they work together to create a precise and robust system that ensures that mitosis is triggered at the right time and in an orderly fashion. In this review, we will give an overview of the literature that describes the Cdk1 activation network and then address questions relating to the systems biology of this switch. How is the timing of the trigger controlled? How is mitosis insulated from interphase? What determines the sequence of events, following the initial trigger of Cdk1 activation? Which elements ensure robustness in the timing and execution of the switch? How has this system been adapted to the high levels of replication stress in cancer cells?

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Section: Organising Mitosis: Open Questions In the Mitotic Entry Fieldmentioning

confidence: 94%

Triggering mitosis

Crncec

Hochegger

2019

FEBS Letters

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“…Thus, the time allocated to the replication process should be flexible enough to limit genome alterations that would result from premature mitotic entry. Cells have indeed developed complex regulatory pathways that permit modulation of the S phase length and retardation of mitotic onset in response to replication impediments, notably through ATR‐mediated activation of CHK1 . Strikingly, the control exerted by ongoing replication on mitotic onset is relatively leaky as a limited number of forks still traveling across late regions escape detection .…”

Section: The Evolution Point Of Viewmentioning

confidence: 99%

A journey with common fragile sites: From S phase to telophase

Debatisse

Rosselli

2018

Genes Chromosomes & Cancer

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Some regions of the genome, notably common fragile sites (CFSs), are hypersensitive to replication stress and often involved in the generation of gross chromosome rearrangements in cancer cells. CFSs nest within very large genes and display cell‐type‐dependent instability. Fragile or not, large genes tend to replicate late in S‐phase. A number of data now show that transcription perturbs replication completion across the body of large genes, particularly upon replication stress. However, the molecular mechanisms by which transcription elicits such under‐replication and subsequent instability remain unclear. We present here our view of the mechanisms responsible for CFS under‐replication and those allowing the cells to cope with this problem in G2 and mitosis. We notably focus on the major role played by the FANC proteins in the protection of CFSs from S phase up to late mitosis. We finally discuss a possible rationale for the conservation of large genes across vertebrate evolution.

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“…Active ATR elicits a checkpoint response by phosphorylating Chk1 and initiating the signalling cascade that culminates with CDK inactivation. The checkpoint response allows DNA repair before committing to mitosis by restricting CDK activity until the S/G2 transition through Chk1 (Lemmens et al, 2018). Cdc25A removes the inhibitory phosphorylation on Tyr15 of CDKs, mediated by the tyrosine kinase Wee1 to prompt CDK activation.…”

Section: Introductionmentioning

confidence: 99%

E2F1 proteolysis via SCF ‐cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition

et al. 2019

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Cyclins are central engines of cell cycle progression in conjunction with cyclin‐dependent kinases (CDKs). Among the different cyclins controlling cell cycle progression, cyclin F does not partner with a CDK, but instead forms via its F‐box domain an SCF (Skp1‐Cul1‐F‐box)‐type E3 ubiquitin ligase module. Although various substrates of cyclin F have been identified, the vulnerabilities of cells lacking cyclin F are not known. Thus, we assessed viability of cells lacking cyclin F upon challenging them with more than 180 different kinase inhibitors. The screen revealed a striking synthetic lethality between Chk1 inhibition and cyclin F loss. Chk1 inhibition in cells lacking cyclin F leads to DNA replication catastrophe. Replication catastrophe depends on accumulation of the transcription factor E2F1 in cyclin F‐depleted cells. We find that SCF‐cyclin F controls E2F1 ubiquitylation and degradation during the G2/M phase of the cell cycle and upon challenging cells with Chk1 inhibitors. Thus, Cyclin F restricts E2F1 activity during the cell cycle and upon checkpoint inhibition to prevent DNA replication stress. Our findings pave the way for patient selection in the clinical use of checkpoint inhibitors.

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

Cited by 107 publications

References 60 publications

Triggering mitosis

Triggering mitosis

A journey with common fragile sites: From S phase to telophase

E2F1 proteolysis via SCF ‐cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition

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