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Evolution of opposing regulatory interactions underlies the emergence of eukaryotic cell cycle checkpoints

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Rosa D. Hernansaiz-Ballesteros, Csenge Földi, Luca Cardelli, László G. Nagy, Attila Csikász-Nagy

Original languageEnglish
Article number11122
JournalScientific Reports
Issue number1
PublishedDec 2021

Bibliographical note

Funding Information: This work was supported by Microsoft Research through its PhD Scholarship Programme, the National Research, Development and Innovation Office of Hungary (K_20 134489), the Thematic Excellence Programme of Hungary (TUDFO/51757-1/2019-ITM), New National Excellence Program of the Ministry of Human Capacities, Hungary (UNKP-19-3-SZTE-79) and the Royal Society (Royal Society Research Professorship RP120138). We want to thank Balázs Bálint for help in reciprocal best hit search, John J. Tyson, Marti Aldea and Rowan Howell for critical reading of the manuscript. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


In eukaryotes the entry into mitosis is initiated by activation of cyclin-dependent kinases (CDKs), which in turn activate a large number of protein kinases to induce all mitotic processes. The general view is that kinases are active in mitosis and phosphatases turn them off in interphase. Kinases activate each other by cross- and self-phosphorylation, while phosphatases remove these phosphate groups to inactivate kinases. Crucial exceptions to this general rule are the interphase kinase Wee1 and the mitotic phosphatase Cdc25. Together they directly control CDK in an opposite way of the general rule of mitotic phosphorylation and interphase dephosphorylation. Here we investigate why this opposite system emerged and got fixed in almost all eukaryotes. Our results show that this reversed action of a kinase-phosphatase pair, Wee1 and Cdc25, on CDK is particularly suited to establish a stable G2 phase and to add checkpoints to the cell cycle. We show that all these regulators appeared together in LECA (Last Eukaryote Common Ancestor) and co-evolved in eukaryotes, suggesting that this twist in kinase-phosphatase regulation was a crucial step happening at the emergence of eukaryotes.

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