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 cyclin-dependent kinases (CycA,B:CDK); and G1 with persistent degradation of CycA,B by Cdh1-activated APC/C (anaphase promoting complex/cyclosome). Because CDKs phosphorylate and inactivate Cdh1, these t...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
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Company of Biologists
2024
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| _version_ | 1811140231652442112 |
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| author | Dragoi, C-M Kaur, E Barr, AR Tyson, JJ Novak, B |
| author_facet | Dragoi, C-M Kaur, E Barr, AR Tyson, JJ Novak, B |
| author_sort | Dragoi, C-M |
| collection | OXFORD |
| description | The mammalian cell cycle alternates between two phases: S-G2-M with high levels of A- and B-type cyclin-dependent kinases (CycA,B:CDK); and G1 with persistent degradation of CycA,B by Cdh1-activated APC/C (anaphase promoting complex/cyclosome). Because CDKs phosphorylate and inactivate Cdh1, these two phases are mutually exclusive. This 'toggle switch' is flipped from G1 to S by cyclin-E (CycE:CDK), which is not degraded by Cdh1:APC/C; and from M to G1 by Cdc20:APC/C, which is not inactivated by CycA,B:CDK. After flipping the switch, cyclin E is degraded and Cdc20:APC/C 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. |
| first_indexed | 2024-03-07T08:19:58Z |
| format | Journal article |
| id | oxford-uuid:4b0ede04-f616-4aaf-a730-12b55357c421 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:18:42Z |
| publishDate | 2024 |
| publisher | Company of Biologists |
| record_format | dspace |
| spelling | oxford-uuid:4b0ede04-f616-4aaf-a730-12b55357c4212024-07-25T09:14:26ZThe oscillation of mitotic kinase governs cell cycle latches in mammalian cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4b0ede04-f616-4aaf-a730-12b55357c421EnglishSymplectic ElementsCompany of Biologists2024Dragoi, C-MKaur, EBarr, ARTyson, JJNovak, BThe mammalian cell cycle alternates between two phases: S-G2-M with high levels of A- and B-type cyclin-dependent kinases (CycA,B:CDK); and G1 with persistent degradation of CycA,B by Cdh1-activated APC/C (anaphase promoting complex/cyclosome). Because CDKs phosphorylate and inactivate Cdh1, these two phases are mutually exclusive. This 'toggle switch' is flipped from G1 to S by cyclin-E (CycE:CDK), which is not degraded by Cdh1:APC/C; and from M to G1 by Cdc20:APC/C, which is not inactivated by CycA,B:CDK. After flipping the switch, cyclin E is degraded and Cdc20:APC/C 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. |
| spellingShingle | Dragoi, C-M Kaur, E Barr, AR Tyson, JJ Novak, B The oscillation of mitotic kinase governs cell cycle latches in mammalian cells |
| title | The oscillation of mitotic kinase governs cell cycle latches in mammalian cells |
| title_full | The oscillation of mitotic kinase governs cell cycle latches in mammalian cells |
| title_fullStr | The oscillation of mitotic kinase governs cell cycle latches in mammalian cells |
| title_full_unstemmed | The oscillation of mitotic kinase governs cell cycle latches in mammalian cells |
| title_short | The oscillation of mitotic kinase governs cell cycle latches in mammalian cells |
| title_sort | oscillation of mitotic kinase governs cell cycle latches in mammalian cells |
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