The oscillation of mitotic kinase governs cell cycle latches in mammalian cells

The mammalian cell cycle alternates between two phases – S-G2-M with high levels of A- and B-type cyclins (CycA and CycB, respectively) bound to cyclin-dependent kinases (CDKs), and G1 with persistent degradation of CycA and CycB by an activated anaphase promoting complex/cyclosome (APC/C) bound to...

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Published inJournal of cell science Vol. 137; no. 3
Main Authors Dragoi, Calin-Mihai, Kaur, Ekjot, Barr, Alexis R., Tyson, John J., Novák, Béla
Format Journal Article
LanguageEnglish
Published England The Company of Biologists Ltd 01.02.2024
Subjects
Anaphase-Promoting Complex-Cyclosome - metabolism
Animals
Cdc20 Proteins - metabolism
Cell Cycle
Cell Cycle Proteins - metabolism
Cyclin-Dependent Kinases - metabolism
Cyclins
Mammals - metabolism
Mitosis
Endocycles
Biochemical switches
Size control
Hysteresis
Bistability
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Abstract The mammalian cell cycle alternates between two phases – S-G2-M with high levels of A- and B-type cyclins (CycA and CycB, respectively) bound to cyclin-dependent kinases (CDKs), and G1 with persistent degradation of CycA and CycB by an activated anaphase promoting complex/cyclosome (APC/C) bound to Cdh1 (also known as FZR1 in mammals; denoted APC/C:Cdh1). Because CDKs phosphorylate and inactivate Cdh1, these two phases are mutually exclusive. This ‘toggle switch’ is flipped from G1 to S by cyclin-E bound to a CDK (CycE:CDK), which is not degraded by APC/C:Cdh1, and from M to G1 by Cdc20-bound APC/C (APC/C:Cdc20), which is not inactivated by CycA:CDK or CycB:CDK. After flipping the switch, cyclin E is degraded and APC/C:Cdc20 is inactivated. Combining mathematical modelling with single-cell timelapse imaging, we show that dysregulation of CycB:CDK disrupts strict alternation of the G1-S and M-G1 switches. Inhibition of CycB:CDK results in Cdc20-independent Cdh1 ‘endocycles’, and sustained activity of CycB:CDK drives Cdh1-independent Cdc20 endocycles. Our model provides a mechanistic explanation for how whole-genome doubling can arise, a common event in tumorigenesis that can drive tumour evolution.
AbstractList The mammalian cell cycle alternates between two phases – S-G2-M with high levels of A- and B-type cyclins (CycA and CycB, respectively) bound to cyclin-dependent kinases (CDKs), and G1 with persistent degradation of CycA and CycB by an activated anaphase promoting complex/cyclosome (APC/C) bound to Cdh1 (also known as FZR1 in mammals; denoted APC/C:Cdh1). Because CDKs phosphorylate and inactivate Cdh1, these two phases are mutually exclusive. This ‘toggle switch’ is flipped from G1 to S by cyclin-E bound to a CDK (CycE:CDK), which is not degraded by APC/C:Cdh1, and from M to G1 by Cdc20-bound APC/C (APC/C:Cdc20), which is not inactivated by CycA:CDK or CycB:CDK. After flipping the switch, cyclin E is degraded and APC/C:Cdc20 is inactivated. Combining mathematical modelling with single-cell timelapse imaging, we show that dysregulation of CycB:CDK disrupts strict alternation of the G1-S and M-G1 switches. Inhibition of CycB:CDK results in Cdc20-independent Cdh1 ‘endocycles’, and sustained activity of CycB:CDK drives Cdh1-independent Cdc20 endocycles. Our model provides a mechanistic explanation for how whole-genome doubling can arise, a common event in tumorigenesis that can drive tumour evolution. Summary: Combining modelling and experimentation, we propose a latching-gate mechanism for strict alternation of DNA replication and mitosis in human cells and show that, if the latches are broken by mutation, then endocycles ensue.
The mammalian cell cycle alternates between two phases - S-G2-M with high levels of A- and B-type cyclins (CycA and CycB, respectively) bound to cyclin-dependent kinases (CDKs), and G1 with persistent degradation of CycA and CycB by an activated anaphase promoting complex/cyclosome (APC/C) bound to Cdh1 (also known as FZR1 in mammals; denoted APC/C:Cdh1). Because CDKs phosphorylate and inactivate Cdh1, these two phases are mutually exclusive. This 'toggle switch' is flipped from G1 to S by cyclin-E bound to a CDK (CycE:CDK), which is not degraded by APC/C:Cdh1, and from M to G1 by Cdc20-bound APC/C (APC/C:Cdc20), which is not inactivated by CycA:CDK or CycB:CDK. After flipping the switch, cyclin E is degraded and APC/C:Cdc20 is inactivated. Combining mathematical modelling with single-cell timelapse imaging, we show that dysregulation of CycB:CDK disrupts strict alternation of the G1-S and M-G1 switches. Inhibition of CycB:CDK results in Cdc20-independent Cdh1 'endocycles', and sustained activity of CycB:CDK drives Cdh1-independent Cdc20 endocycles. Our model provides a mechanistic explanation for how whole-genome doubling can arise, a common event in tumorigenesis that can drive tumour evolution.The mammalian cell cycle alternates between two phases - S-G2-M with high levels of A- and B-type cyclins (CycA and CycB, respectively) bound to cyclin-dependent kinases (CDKs), and G1 with persistent degradation of CycA and CycB by an activated anaphase promoting complex/cyclosome (APC/C) bound to Cdh1 (also known as FZR1 in mammals; denoted APC/C:Cdh1). Because CDKs phosphorylate and inactivate Cdh1, these two phases are mutually exclusive. This 'toggle switch' is flipped from G1 to S by cyclin-E bound to a CDK (CycE:CDK), which is not degraded by APC/C:Cdh1, and from M to G1 by Cdc20-bound APC/C (APC/C:Cdc20), which is not inactivated by CycA:CDK or CycB:CDK. After flipping the switch, cyclin E is degraded and APC/C:Cdc20 is inactivated. Combining mathematical modelling with single-cell timelapse imaging, we show that dysregulation of CycB:CDK disrupts strict alternation of the G1-S and M-G1 switches. Inhibition of CycB:CDK results in Cdc20-independent Cdh1 'endocycles', and sustained activity of CycB:CDK drives Cdh1-independent Cdc20 endocycles. Our model provides a mechanistic explanation for how whole-genome doubling can arise, a common event in tumorigenesis that can drive tumour evolution.
The mammalian cell cycle alternates between two phases – S-G2-M with high levels of A- and B-type cyclins (CycA and CycB, respectively) bound to cyclin-dependent kinases (CDKs), and G1 with persistent degradation of CycA and CycB by an activated anaphase promoting complex/cyclosome (APC/C) bound to Cdh1 (also known as FZR1 in mammals; denoted APC/C:Cdh1). Because CDKs phosphorylate and inactivate Cdh1, these two phases are mutually exclusive. This ‘toggle switch’ is flipped from G1 to S by cyclin-E bound to a CDK (CycE:CDK), which is not degraded by APC/C:Cdh1, and from M to G1 by Cdc20-bound APC/C (APC/C:Cdc20), which is not inactivated by CycA:CDK or CycB:CDK. After flipping the switch, cyclin E is degraded and APC/C:Cdc20 is inactivated. Combining mathematical modelling with single-cell timelapse imaging, we show that dysregulation of CycB:CDK disrupts strict alternation of the G1-S and M-G1 switches. Inhibition of CycB:CDK results in Cdc20-independent Cdh1 ‘endocycles’, and sustained activity of CycB:CDK drives Cdh1-independent Cdc20 endocycles. Our model provides a mechanistic explanation for how whole-genome doubling can arise, a common event in tumorigenesis that can drive tumour evolution.
Author Dragoi, Calin-Mihai
Novák, Béla
Barr, Alexis R.
Tyson, John J.
Kaur, Ekjot
AuthorAffiliation 3 Institute of Clinical Sciences, Imperial College London , Du Cane Road, London W12 0NN , UK
2 MRC London Institute of Medical Sciences, Hammersmith Hospital Campus , Du Cane Road, London W12 0NN , UK
1 Department of Biochemistry , University of Oxford , South Parks Road, Oxford OX1 3QU , UK
4 Department of Biological Sciences , Virginia Tech , Blacksburg, VA 24061 , USA
AuthorAffiliation_xml – name: 4 Department of Biological Sciences , Virginia Tech , Blacksburg, VA 24061 , USA
– name: 2 MRC London Institute of Medical Sciences, Hammersmith Hospital Campus , Du Cane Road, London W12 0NN , UK
– name: 3 Institute of Clinical Sciences, Imperial College London , Du Cane Road, London W12 0NN , UK
– name: 1 Department of Biochemistry , University of Oxford , South Parks Road, Oxford OX1 3QU , UK
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Issue 3
Keywords Endocycles
Biochemical switches
Size control
Hysteresis
Bistability
Language English
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2024. Published by The Company of Biologists Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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Handling Editor: David Stephens
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Snippet The mammalian cell cycle alternates between two phases – S-G2-M with high levels of A- and B-type cyclins (CycA and CycB, respectively) bound to...
The mammalian cell cycle alternates between two phases - S-G2-M with high levels of A- and B-type cyclins (CycA and CycB, respectively) bound to...
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SubjectTerms Anaphase-Promoting Complex-Cyclosome - metabolism
Animals
Cdc20 Proteins - metabolism
Cell Cycle
Cell Cycle Proteins - metabolism
Cyclin-Dependent Kinases - metabolism
Cyclins
Mammals - metabolism
Mitosis
Title The oscillation of mitotic kinase governs cell cycle latches in mammalian cells
URI https://www.ncbi.nlm.nih.gov/pubmed/38206091
https://www.proquest.com/docview/2913446513
https://pubmed.ncbi.nlm.nih.gov/PMC10911285
Volume 137
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