Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Hernansaiz-Ballesteros RD

PROVIDER: S-EPMC8159995 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Hernansaiz-Ballesteros Rosa D RD Földi Csenge C Cardelli Luca L Nagy László G LG Csikász-Nagy Attila A

Scientific reports 20210527 1

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 an ...[more]

PMID: 34045495

Similar Datasets

Project description:BackgroundCell cycle process of budding yeast (Saccharomyces cerevisiae) consists of four phases: G1, S, G2 and M. Initiated by stimulation of the G1 phase, cell cycle returns to the G1 stationary phase through a sequence of the S, G2 and M phases. During the cell cycle, a cell verifies whether necessary conditions are satisfied at the end of each phase (i.e., checkpoint) since damages of any phase can cause severe cell cycle defect. The cell cycle can proceed to the next phase properly only if checkpoint conditions are met. Over the last decade, there have been several studies to construct Boolean models that capture checkpoint conditions. However, they mostly focused on robustness to network perturbations, and the timing robustness has not been much addressed. Only recently, some studies suggested extension of such models towards timing-robust models, but they have not considered checkpoint conditions.ResultsTo construct a timing-robust Boolean model that preserves checkpoint conditions of the budding yeast cell cycle, we used a model verification technique, 'model checking'. By utilizing automatic and exhaustive verification of model checking, we found that previous models cannot properly capture essential checkpoint conditions in the presence of timing variations. In particular, such models violate the M phase checkpoint condition so that it allows a division of a budding yeast cell into two before the completion of its full DNA replication and synthesis. In this paper, we present a timing-robust model that preserves all the essential checkpoint conditions properly against timing variations. Our simulation results show that the proposed timing-robust model is more robust even against network perturbations and can better represent the nature of cell cycle than previous models.ConclusionsTo our knowledge this is the first work that rigorously examined the timing robustness of the cell cycle process of budding yeast with respect to checkpoint conditions using Boolean models. The proposed timing-robust model is the complete state-of-the-art model that guarantees no violation in terms of checkpoints known to date.

Project description:BACKGROUND: Impaired proliferation of hepatocytes has been reported in chronic Hepatitis C virus infection. Considering the fundamental role played by cell cycle proteins in controlling cell proliferation, altered regulation of these proteins could significantly contribute to HCV disease progression and subsequent hepatocellular carcinoma (HCC). This study aimed to identify the alterations in cell cycle genes expression with respect to early and advanced disease of chronic HCV infection. METHODS: Using freshly frozen liver biopsies, mRNA levels of 84 cell cycle genes in pooled RNA samples from patients with early or advanced fibrosis of chronic HCV infection were studied. To associate mRNA levels with respective protein levels, four genes (p27, p15, KNTC1 and MAD2L1) with significant changes in mRNA levels (> 2-fold, p-value < 0.05) were selected, and their protein expressions were examined in the liver biopsies of 38 chronic hepatitis C patients. RESULTS: In the early fibrosis group, increased mRNA levels of cell proliferation genes as well as cell cycle inhibitor genes were observed. In the advanced fibrosis group, DNA damage response genes were up-regulated while those associated with chromosomal stability were down-regulated. Increased expression of CDK inhibitor protein p27 was consistent with its mRNA level detected in early group while the same was found to be negatively associated with liver fibrosis. CDK inhibitor protein p15 was highly expressed in both early and advanced group, but showed no correlation with fibrosis. Among the mitotic checkpoint regulators, expression of KNTC1 was significantly reduced in advanced group while MAD2L1 showed a non-significant decrease. CONCLUSION: Collectively these results are suggestive of a disrupted cell cycle regulation in HCV-infected liver. The information presented here highlights the potential of identified proteins as predictive factors to identify patients with high risk of cell transformation and HCC development.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets