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

Author(s)

Lazari, Lucas Cardoso ; Wolf, Ivan Rodrigo ; Schnepper, Amanda Piveta ; Valente, Guilherme Targino

• Document type: Journal article
• Source: PLOS COMPUTATIONAL BIOLOGY; v. 18, n. 5, p. 29-pg., 2022-05-01.

Abstract

Author summaryEthanol is a cell stressor in yeast that dampen ethanol production. LncRNAs are RNAs that control many cellular processes. Computational simulations allow us to study the dynamism of cell systems. Therefore, we built a computational model of the yeast cell cycle to investigate how cells respond to ethanol stress. Simulations showed that ethanol stress or spindle damage arrests the cell cycle. Furthermore, the performance of higher and lower ethanol-tolerant strains in poststress recovery growth seems to be related to the cell cycle phase in which cells are stalled. However, two lncRNAs maintain the activity of the cell cycle even in yeast cells under these stresses by repressing specific cell cycle proteins. Finally, this model facilitates analyses of the yeast cell cycle for applied or basic science purposes. Ethanol alters many subsystems of Saccharomyces cerevisiae, including the cell cycle. Two ethanol-responsive lncRNAs in yeast interact with cell cycle proteins, and here, we investigated the role of these RNAs in cell cycle. Our network dynamic modeling showed that higher and lower ethanol-tolerant strains undergo cell cycle arrest in mitosis and G1 phases, respectively, during ethanol stress. The higher population rebound of the lower ethanol-tolerant phenotype after stress relief responds to the late phase arrest. We found that the lncRNA lnc9136 of SEY6210 (a lower ethanol-tolerant strain) induces cells to skip mitosis arrest. Simulating an overexpression of lnc9136 and analyzing CRISPR-Cas9 mutants lacking this lncRNA suggest that lnc9136 induces a regular cell cycle even under ethanol stress, indirectly regulating Swe1p and Clb1/2 by binding to Gin4p and Hsl1p. Notably, lnc10883 of BY4742 (a higher ethanol-tolerant strain) does not prevent G1 arrest in this strain under ethanol stress. However, lnc19883 circumvents DNA and spindle damage checkpoints, maintaining a functional cell cycle by interacting with Mec1p or Bub1p even in the presence of DNA/spindle damage. Overall, we present the first evidence of direct roles for lncRNAs in regulating yeast cell cycle proteins, the dynamics of this system in different ethanol-tolerant phenotypes, and a new yeast cell cycle model. (AU)

• FAPESP's process: 15/19211-7 - Identification of systemic signatures associated to ethanol tolerance in Saccharomyces cerevisiae strains
• Grantee: Ivan Rodrigo Wolf
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 17/08463-0 - Systems biology and synthetic biology to re-engineering metabolic pathways in Saccharomyces cerevisiae: dealing with ethanol tolerance
• Grantee: Guilherme Targino Valente
• Support Opportunities: Program for Research on Bioenergy (BIOEN) - Regular Program Grants
• FAPESP's process: 15/12093-9 - Integrative analysis applied to ethanol tolerance in Saccharomyces cerevisiae strains: an approach using transcriptomes, proteomes, system biology and machine learning
• Grantee: Guilherme Targino Valente
• Support Opportunities: Program for Research on Bioenergy (BIOEN) - Regular Program Grants