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CDK control pathways integrate cell size and ploidy information to control cell division

James Oliver Patterson, Souradeep Basu, Paul Rees Orcid Logo, Paul Nurse

eLife, Volume: 10

Swansea University Author: Paul Rees Orcid Logo

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DOI (Published version): 10.7554/elife.64592

Abstract

Maintenance of cell size homeostasis is a property that is conserved throughout eukaryotes. Cell size homeostasis is brought about by the co-ordination of cell division with cell growth and requires restriction of smaller cells from undergoing mitosis and cell division, whilst allowing larger cells...

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Published in: eLife
ISSN: 2050-084X
Published: eLife Sciences Publications, Ltd 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa57132
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first_indexed 2021-06-15T18:52:44Z
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Cyclin-CDK is the fundamental driver of mitosis and therefore ultimately ensures size homeostasis. Here we dissect determinants of CDK activity in vivo to investigate how cell size information is processed by the cell cycle network in fission yeast. We develop a high-throughput single-cell assay system of CDK activity in vivo and show that inhibitory tyrosine phosphorylation of CDK encodes cell size information, with the phosphatase PP2A aiding to set a size threshold for division. CDK inhibitory phosphorylation works synergistically with PP2A to prevent mitosis in smaller cells. Finally, we find that diploid cells of equivalent size to haploid cells exhibit lower CDK activity in response to equal cyclin-CDK enzyme concentrations, suggesting that CDK activity is reduced by increased DNA levels. Therefore, scaling of cyclin-CDK levels with cell size, CDK inhibitory phosphorylation, PP2A, and DNA-dependent inhibition of CDK activity, all inform the cell cycle network of cell size, thus contributing to cell size homeostasis.</abstract><type>Journal Article</type><journal>eLife</journal><volume>10</volume><journalNumber/><paginationStart/><paginationEnd/><publisher>eLife Sciences Publications, Ltd</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2050-084X</issnElectronic><keywords/><publishedDay>1</publishedDay><publishedMonth>7</publishedMonth><publishedYear>2021</publishedYear><publishedDate>2021-07-01</publishedDate><doi>10.7554/elife.64592</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Engineering</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDE</DepartmentCode><institution>Swansea University</institution><apcterm/><funders>We thank Jessica Greenwood and Clovis Basier for their extensive efforts in editing the manuscript. This work was supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (FC01121), the UK Medical Research Council (FC01121), and the Wellcome Trust (FC01121). In addition, this work was supported by the Wellcome Trust Grant to PN (grant number 214183 and 093917), The Lord Leonard and Lady Estelle Wolfson Foundation, and Woosnam Foundation. JOP and PR acknowledge the support of the Biotechnology and Biological Sciences Research Council under grant BB/P026818/1. PR also acknowledges the support of the Biotechnology and Biological Sciences Research Council/National Science Foundation under grant BB/N005163/1 and NSF DBI 1458626. 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spelling 2022-07-05T13:04:45.8441935 v2 57132 2021-06-15 CDK control pathways integrate cell size and ploidy information to control cell division 537a2fe031a796a3bde99679ee8c24f5 0000-0002-7715-6914 Paul Rees Paul Rees true false 2021-06-15 MEDE Maintenance of cell size homeostasis is a property that is conserved throughout eukaryotes. Cell size homeostasis is brought about by the co-ordination of cell division with cell growth and requires restriction of smaller cells from undergoing mitosis and cell division, whilst allowing larger cells to do so. Cyclin-CDK is the fundamental driver of mitosis and therefore ultimately ensures size homeostasis. Here we dissect determinants of CDK activity in vivo to investigate how cell size information is processed by the cell cycle network in fission yeast. We develop a high-throughput single-cell assay system of CDK activity in vivo and show that inhibitory tyrosine phosphorylation of CDK encodes cell size information, with the phosphatase PP2A aiding to set a size threshold for division. CDK inhibitory phosphorylation works synergistically with PP2A to prevent mitosis in smaller cells. Finally, we find that diploid cells of equivalent size to haploid cells exhibit lower CDK activity in response to equal cyclin-CDK enzyme concentrations, suggesting that CDK activity is reduced by increased DNA levels. Therefore, scaling of cyclin-CDK levels with cell size, CDK inhibitory phosphorylation, PP2A, and DNA-dependent inhibition of CDK activity, all inform the cell cycle network of cell size, thus contributing to cell size homeostasis. Journal Article eLife 10 eLife Sciences Publications, Ltd 2050-084X 1 7 2021 2021-07-01 10.7554/elife.64592 COLLEGE NANME Biomedical Engineering COLLEGE CODE MEDE Swansea University We thank Jessica Greenwood and Clovis Basier for their extensive efforts in editing the manuscript. This work was supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (FC01121), the UK Medical Research Council (FC01121), and the Wellcome Trust (FC01121). In addition, this work was supported by the Wellcome Trust Grant to PN (grant number 214183 and 093917), The Lord Leonard and Lady Estelle Wolfson Foundation, and Woosnam Foundation. JOP and PR acknowledge the support of the Biotechnology and Biological Sciences Research Council under grant BB/P026818/1. PR also acknowledges the support of the Biotechnology and Biological Sciences Research Council/National Science Foundation under grant BB/N005163/1 and NSF DBI 1458626. JOP acknowledges support from the Boehringer Ingelheim Fonds PhD fellowship. 2022-07-05T13:04:45.8441935 2021-06-15T19:50:35.3134817 Faculty of Science and Engineering School of Engineering and Applied Sciences - Biomedical Engineering James Oliver Patterson 1 Souradeep Basu 2 Paul Rees 0000-0002-7715-6914 3 Paul Nurse 4 57132__20327__f41eb521310f4dffbf33ab64195be467.pdf 57132.pdf 2021-07-05T09:13:58.5881419 Output 5674480 application/pdf Version of Record true © 2021, Patterson et al. This article is distributed under the terms of the Creative Commons Attribution License true eng http://creativecommons.org/licenses/by/4.0/ 102 Paul Nurse true https://figshare.com/s/bdc29f893e7153c0e859 false
title CDK control pathways integrate cell size and ploidy information to control cell division
spellingShingle CDK control pathways integrate cell size and ploidy information to control cell division
Paul Rees
title_short CDK control pathways integrate cell size and ploidy information to control cell division
title_full CDK control pathways integrate cell size and ploidy information to control cell division
title_fullStr CDK control pathways integrate cell size and ploidy information to control cell division
title_full_unstemmed CDK control pathways integrate cell size and ploidy information to control cell division
title_sort CDK control pathways integrate cell size and ploidy information to control cell division
author_id_str_mv 537a2fe031a796a3bde99679ee8c24f5
author_id_fullname_str_mv 537a2fe031a796a3bde99679ee8c24f5_***_Paul Rees
author Paul Rees
author2 James Oliver Patterson
Souradeep Basu
Paul Rees
Paul Nurse
format Journal article
container_title eLife
container_volume 10
publishDate 2021
institution Swansea University
issn 2050-084X
doi_str_mv 10.7554/elife.64592
publisher eLife Sciences Publications, Ltd
college_str Faculty of Science and Engineering
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hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Biomedical Engineering{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Biomedical Engineering
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description Maintenance of cell size homeostasis is a property that is conserved throughout eukaryotes. Cell size homeostasis is brought about by the co-ordination of cell division with cell growth and requires restriction of smaller cells from undergoing mitosis and cell division, whilst allowing larger cells to do so. Cyclin-CDK is the fundamental driver of mitosis and therefore ultimately ensures size homeostasis. Here we dissect determinants of CDK activity in vivo to investigate how cell size information is processed by the cell cycle network in fission yeast. We develop a high-throughput single-cell assay system of CDK activity in vivo and show that inhibitory tyrosine phosphorylation of CDK encodes cell size information, with the phosphatase PP2A aiding to set a size threshold for division. CDK inhibitory phosphorylation works synergistically with PP2A to prevent mitosis in smaller cells. Finally, we find that diploid cells of equivalent size to haploid cells exhibit lower CDK activity in response to equal cyclin-CDK enzyme concentrations, suggesting that CDK activity is reduced by increased DNA levels. Therefore, scaling of cyclin-CDK levels with cell size, CDK inhibitory phosphorylation, PP2A, and DNA-dependent inhibition of CDK activity, all inform the cell cycle network of cell size, thus contributing to cell size homeostasis.
published_date 2021-07-01T04:12:38Z
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