LncRNAs of Saccharomyces cerevisiae dodge the cell cycle arrest imposed by the ethanol stress

Ethanol impairs many subsystems of Saccharomyces cerevisiae, including the cell cycle. Cyclins and damage checkpoints drive the cell cycle. Two ethanol-responsive lncRNAs in yeast interact with cell cycle proteins, and here we investigated the role of these RNAs on the ethanol-stressed cell cycle. Our network dynamic modeling showed that the higher and lower ethanol tolerant strains undergo a cell cycle arrest during the ethanol stress. However, lower tolerant phenotype arrest in a later phase leading to its faster population rebound after the stress relief. Two lncRNAs can skip the arrests mentioned. The in silico overexpression of lnc9136 of SEY6210 (a lower tolerant strain), and CRISPR-Cas9 partial deletions of this lncRNA, evidenced that the one induces a regular cell cycle even under ethanol stress; this lncRNA binds to Gin4 and Hsl1, driving the Swe1p, Clb1/2, and cell cycle. Moreover, the lnc10883 of BY4742 (a higher tolerant strain) interacts to the Mec1p and represses Bub1p, circumventing the DNA and spindle damage checkpoints keeping a normal cell cycle even under DNA damage. Overall, we present the first evidence of the direct roles of lncRNAs on cell cycle proteins, the dynamics of this system in different ethanol tolerant phenotypes, and a new cell cycle model.

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Proteotoxic Stress Induces a Cell-Cycle Arrest by Stimulating Lon to Degrade the Replication Initiator DnaA

Cell ◽

10.1016/j.cell.2013.06.034 ◽

2013 ◽

Vol 154 (3) ◽

pp. 623-636 ◽

Cited By ~ 103

Author(s):

Kristina Jonas ◽

Jing Liu ◽

Peter Chien ◽

Michael T. Laub

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Proteotoxic Stress ◽

Cycle Arrest ◽

A Cell ◽

Replication Initiator

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Dominant negative selection of heterologous genes: isolation of Candida albicans genes that interfere with Saccharomyces cerevisiae mating factor-induced cell cycle arrest.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.89.20.9410 ◽

1992 ◽

Vol 89 (20) ◽

pp. 9410-9414 ◽

Cited By ~ 92

Author(s):

M. Whiteway ◽

D. Dignard ◽

D. Y. Thomas

Keyword(s):

Saccharomyces Cerevisiae ◽

Cell Cycle ◽

Candida Albicans ◽

Cell Cycle Arrest ◽

Negative Selection ◽

Dominant Negative ◽

Cycle Arrest ◽

Mating Factor ◽

Selection Of

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The Resveratrol Tetramer r-Viniferin Induces a Cell Cycle Arrest Followed by Apoptosis in the Prostate Cancer Cell Line LNCaP

Phytotherapy Research ◽

10.1002/ptr.5443 ◽

2015 ◽

Vol 29 (10) ◽

pp. 1640-1645 ◽

Cited By ~ 14

Author(s):

Michael T. Empl ◽

Malena Albers ◽

Shan Wang ◽

Pablo Steinberg

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cell Line ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Cancer Cell Line ◽

Prostate Cancer Cell Line ◽

Cycle Arrest ◽

A Cell

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The ORC/Cdc6/MCM2-7 complex facilitates MCM2-7 dimerization during prereplicative complex formation

Nucleic Acids Research ◽

10.1093/nar/gkt1148 ◽

2013 ◽

Vol 42 (4) ◽

pp. 2257-2269 ◽

Cited By ~ 21

Author(s):

Cecile Evrin ◽

Alejandra Fernández-Cid ◽

Alberto Riera ◽

Juergen Zech ◽

Pippa Clarke ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Cell Cycle ◽

Complex Formation ◽

Cell Cycle Arrest ◽

Atp Hydrolysis ◽

Cycle Arrest ◽

Helicase Loading ◽

Limiting Step ◽

Prereplicative Complex ◽

Dominant Lethality

Abstract The replicative mini-chromosome-maintenance 2–7 (MCM2-7) helicase is loaded in Saccharomyces cerevisiae and other eukaryotes as a head-to-head double-hexamer around origin DNA. At first, ORC/Cdc6 recruits with the help of Cdt1 a single MCM2-7 hexamer to form an ‘initial’ ORC/Cdc6/Cdt1/MCM2-7 complex. Then, on ATP hydrolysis and Cdt1 release, the ‘initial’ complex is transformed into an ORC/Cdc6/MCM2-7 (OCM) complex. However, it remains unclear how the OCM is subsequently converted into a MCM2-7 double-hexamer. Through analysis of MCM2-7 hexamer-interface mutants we discovered a complex competent for MCM2-7 dimerization. We demonstrate that these MCM2-7 mutants arrest during prereplicative complex (pre-RC) assembly after OCM formation, but before MCM2-7 double-hexamer assembly. Remarkably, only the OCM complex, but not the ‘initial’ ORC/Cdc6/Cdt1/MCM2-7 complex, is competent for MCM2-7 dimerization. The MCM2-7 dimer, in contrast to the MCM2-7 double-hexamer, interacts with ORC/Cdc6 and is salt-sensitive, classifying the arrested complex as a helicase-loading intermediate. Accordingly, we found that overexpression of the mutants cause cell-cycle arrest and dominant lethality. Our work identifies the OCM complex as competent for MCM2-7 dimerization, reveals MCM2-7 dimerization as a limiting step during pre-RC formation and defines critical mechanisms that explain how origins are licensed.

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Role of Cdc42-Cla4 Interaction in the Pheromone Response of Saccharomyces cerevisiae

Eukaryotic Cell ◽

10.1128/ec.00102-06 ◽

2006 ◽

Vol 6 (2) ◽

pp. 317-327 ◽

Cited By ~ 17

Author(s):

Melanie Heinrich ◽

Tim Köhler ◽

Hans-Ulrich Mösch

Keyword(s):

Saccharomyces Cerevisiae ◽

Cell Cycle ◽

Map Kinase ◽

Cell Cycle Arrest ◽

Map Kinases ◽

Negative Regulator ◽

Cycle Arrest ◽

Mitogen Activated Protein ◽

Novel Alleles

ABSTRACT In Saccharomyces cerevisiae, the highly conserved Rho-type GTPase Cdc42 is essential for cell division and controls cellular development during mating and invasive growth. The role of Cdc42 in mating has been controversial, but a number of previous studies suggest that the GTPase controls the mitogen-activated protein (MAP) kinase cascade by activating the p21-activated protein kinase (PAK) Ste20. To further explore the role of Cdc42 in pheromone-stimulated signaling, we isolated novel alleles of CDC42 that confer resistance to pheromone. We find that in CDC42(V36A) and CDC42(V36A, I182T) mutant strains, the inability to undergo pheromone-induced cell cycle arrest correlates with reduced phosphorylation of the mating MAP kinases Fus3 and Kss1 and with a decrease in mating efficiency. Furthermore, Cdc42(V36A) and Cdc42(V36A, I182T) proteins show reduced interaction with the PAK Cla4 but not with Ste20. We also show that deletion of CLA4 in a CDC42(V36A, I182T) mutant strain suppresses pheromone resistance and that overexpression of CLA4 interferes with pheromone-induced cell cycle arrest and MAP kinase phosphorylation in CDC42 wild-type strains. Our data indicate that Cla4 has the potential to act as a negative regulator of the mating pathway and that this function of the PAK might be under control of Cdc42. In conclusion, our study suggests that control of pheromone signaling by Cdc42 not only depends on Ste20 but also involves interaction of the GTPase with Cla4.

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Induction of apoptosis by flavopiridol (FP) independent of a cell cycle arrest in germ cell tumor (GCT) cell lines

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.14_suppl.9712 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 9712-9712

Author(s):

F. Mayer ◽

S. Koch ◽

E. Malenke ◽

C. Bokemeyer

Keyword(s):

Cell Cycle ◽

Germ Cell ◽

Cell Cycle Arrest ◽

Cell Lines ◽

Germ Cell Tumor ◽

Cell Tumor ◽

Cycle Arrest ◽

A Cell ◽

Induction Of Apoptosis

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Exploratory analysis of the effect of taselisib on downstream pathway modulation and correlation with tumor response in ER-positive/HER2-negative early-stage breast cancer from the LORELEI trial.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.1050 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 1050-1050 ◽

Cited By ~ 1

Author(s):

Paolo Nuciforo ◽

Dominik Hlauschek ◽

Cristina Saura ◽

Evandro de Azambuja ◽

Roberta Fasani ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Early Stage ◽

Objective Response ◽

Wild Type ◽

Cycle Arrest ◽

Er Positive ◽

A Cell ◽

Tumor Biopsies ◽

Clinical Trial Information

1050 Background: Taselisib (T) is an oral, potent, selective inhibitor of Class I PI3-kinase with enhanced activity against PIK3CA mutant cancer cells. Results from the LORELEI trial have demonstrated a significant improvement in ORR (objective response rate) by centrally assessed magnetic resonance imaging in all randomized patients as well as in the PIK3CA mutant (MT) cohort treated with neoadjuvant T plus letrozole (L) compared to placebo (P) plus L. Here we present the results of exploratory analyses of selected pathway-related phosphoproteins. Methods: Baseline (BL) and week3 (W3) tumor biopsies were obtained from 334 patients enrolled in the trial. Phosphoproteins (pAKT, pPRAS40 and pS6) were analyzed by IHC. BL levels as well as changes from BL to W3 were correlated with response assessed either by ORR or cell cycle arrest (Ki67 at W3 < 2.7%). Results: In the overall population, BL phosphoproteins levels were similar between the T and P arms. Higher pAKT (p < 0.001) and pPRAS40 (p = 0.004) levels were observed in MT vs wild-type (WT), whereas the opposite result was found for pS6 (p = 0.03). Treatment-induced absolute changes of phosphoproteins adjusted for BL levels were not significantly different between the T and P arms in the overall population, except for pPRAS40 with higher decrease in the T arm (p = 0.014). After stratification for PIK3CA genotype, a significantly greater decrease in expression levels was observed for pPRAS40 (p < 0.001) and pS6 (p = 0.020) in MT tumors treated with T. The treatment effects were not significantly different in the WT population. A trend for an association between decrease in pS6 levels at W3 and improved ORR was observed in the MT (p = 0.08) and T (p = 0.09) subgroups. The magnitude of pS6 suppression at W3 was higher in tumors achieving a cell cycle arrest in the MT/T subgroup (biserial correlation = -0.473). Conclusions: Exploratory analyses of phosphoproteins showed bioactivity of taselisib as indicated by downstream pathway suppression. Translational research aiming to integrate these results with additional exploratory biomarkers data is currently ongoing. Clinical trial information: NCT02273973.

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RPA provides checkpoint-independent cell cycle arrest and prevents recombination at uncapped telomeres of Saccharomyces cerevisiae

DNA Repair ◽

10.1016/j.dnarep.2012.12.002 ◽

2013 ◽

Vol 12 (3) ◽

pp. 212-226 ◽

Cited By ~ 1

Author(s):

Nathalie Grandin ◽

Michel Charbonneau

Keyword(s):

Saccharomyces Cerevisiae ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cycle Arrest

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Differential transmission of G1 cell cycle arrest and mating signals by Saccharomyces cerevisiae Ste5 mutants in the pheromone pathway

Biochemistry and Cell Biology ◽

10.1139/o99-054 ◽

1999 ◽

Vol 77 (5) ◽

pp. 459-468

Author(s):

You-Jeong Choi ◽

Sun-Hong Kim ◽

Ki-Sook Park ◽

Kang-Yell Choi

Keyword(s):

Saccharomyces Cerevisiae ◽

Cell Cycle ◽

Signal Transduction ◽

Cell Cycle Arrest ◽

Mitogen Activated Protein Kinase ◽

Chemical Mutagenesis ◽

G1 Arrest ◽

Cycle Arrest ◽

Isolation And Characterization ◽

G1 Cell Cycle Arrest

Saccharomyces cerevisiae Ste5 is a scaffold protein that recruits many pheromone signaling molecules to sequester the pheromone pathway from other homologous mitogen-activated protein kinase pathways. G1 cell cycle arrest and mating are two different physiological consequences of pheromone signal transduction and Ste5 is required for both processes. However, the roles of Ste5 in G1 arrest and mating are not fully understood. To understand the roles of Ste5 better, we isolated 150 G1 cell cycle arrest defective STE5 mutants by chemical mutagenesis of the gene. Here, we found that two G1 cell cycle arrest defective STE5 mutants (ste5MD248V and ste5delta-776) retained mating capacity. When overproduced in a wild-type strain, several ste5 mutants also showed different dominant phenotypes for G1 arrest and mating. Isolation and characterization of the mutants suggested separable roles of Ste5 in G1 arrest and mating of S. cerevisiae. In addition, the roles of Asp-248 and Tyr-421, which are important for pheromone signal transduction were further characterized by site-directed mutagenesis studies.Key words: Ste5, Saccharomyces cerevisiae, signal transduction, mating, G1 cell cycle arrest.

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