Spatiotemporal control of mitotic exit during anaphase by an Aurora B-Cdk1 crosstalk

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Abstract

According to the prevailing 'clock' model, chromosome decondensation and nuclear envelope reformation when cells exit mitosis are byproducts of Cdk1 inactivation at the metaphase-anaphase transition, controlled by the spindle assembly checkpoint. However, mitotic exit was recently shown to be a function of chromosome separation during anaphase, assisted by a midzone Aurora B phosphorylation gradient - the 'ruler' model. Here we found that Cdk1 remains active during anaphase due to ongoing APC/C^Cdc20- and APC/C^Cdh1-mediated degradation of B-type Cyclins in Drosophila and human cells. Failure to degrade B-type Cyclins during anaphase prevented mitotic exit in a Cdk1-dependent manner. Cyclin B1-Cdk1 localized at the spindle midzone in an Aurora B-dependent manner, with incompletely separated chromosomes showing the highest Cdk1 activity. Slowing down anaphase chromosome motion delayed Cyclin B1 degradation and mitotic exit in an Aurora B-dependent manner. Thus, a crosstalk between molecular 'rulers' and 'clocks' licenses mitotic exit only after proper chromosome separation.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Olga Afonso

Chromosome Instability and Dynamics Laboratory, Instituto de Biologia Molecular e Celular, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

Competing interests
The authors declare that no competing interests exist.
Colleen M Castellani

Biology Department, University of Massachusetts, Amherst, United States

Competing interests
The authors declare that no competing interests exist.
Liam P Cheeseman

Chromosome Instability and Dynamics Laboratory, Instituto de Biologia Molecular e Celular, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

Competing interests
The authors declare that no competing interests exist.
Jorge G Ferreira

Chromosome Instability and Dynamics Laboratory, Instituto de Biologia Molecular e Celular, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

Competing interests
The authors declare that no competing interests exist.
Bernardo Orr

Chromosome Instability and Dynamics Laboratory, Instituto de Biologia Molecular e Celular, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

Competing interests
The authors declare that no competing interests exist.
Luisa T Ferreira

Chromosome Instability and Dynamics Laboratory, Instituto de Biologia Molecular e Celular, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

Competing interests
The authors declare that no competing interests exist.
James J Chambers

Institute for Applied Life Sciences,, University of Massachusetts, Amherst, United States

Competing interests
The authors declare that no competing interests exist.
Eurico Morais-de-Sá

Chromosome Instability and Dynamics Laboratory, Instituto de Biologia Molecular e Celular, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

Competing interests
The authors declare that no competing interests exist.
Thomas J Maresca

Biology Department, University of Massachusetts, Amherst, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2214-8674
Helder Maiato

Chromosome Instability and Dynamics Laboratory, Instituto de Biologia Molecular e Celular, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

For correspondence
maiato@i3s.up.pt

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6200-9997

Funding

European Reseach Council (681443)

Helder Maiato

Fundação Luso-Americana (FLAD LifeScience2020)

Helder Maiato

Marie Skłodowska-Curie Action (746515)

Liam P Cheeseman

Fundação para a Ciência e a Tecnologia (PTDC/BEX-BCM/0432/2014)

Eurico Morais-de-Sá

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mice were maintained in a specific pathogen-free environment according to the Portuguese animal welfare authority regulations (Direcção Geral de Alimentação e Veterinária; reference# 0421/000/000/2016) and the guidelines of the Instituto de Investigação e Inovação em Saúde animal facility.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.