A Novel Sterol-Signaling Pathway Governs Azole Antifungal Drug Resistance and Hypoxic Gene Repression in <i>Saccharomyces cerevisiae</i>

Serratore, Nina D.; Baker, Kortany M; Macadlo, Lauren A; Gress, Abigail R; Powers, Brendan L.; Atallah, Nadia M.; Westerhouse, Kirsten M; Hall, Mark C.; Weake, Vikki M.; Briggs, Scott

doi:10.1534/genetics.117.300554

Cited by 33 publications

(80 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although our observation that Set4 promotes full activation of ERG genes in aerobic conditions in rich medium appears contradictory to the finding that Set4 promotes repression of ERG genes during chronic hypoxia in rich medium (38), this discrepancy may be explained by condition-specific functions of Set4 and may underscore potentially different roles in acute stress (short H 2 O 2 treatment) versus chronic stress. Set4 may be able to both activate and repress genes, particularly in a condition-specific manner.…”

Section: Set4 Protects Cells During Oxidative Stresscontrasting

confidence: 99%

“…Given that increased membrane permeability sensitizes cells to exogenous H 2 O 2 (36), another plausible mechanism for Set4-mediated protection in the presence of H 2 O 2 could be the regulation of ergosterol biosynthetic genes, which control the levels of the plasma membrane sterol, ergosterol, in yeast. A recent report found that Set4 represses ERG genes during hypoxia, in a manner dependent on the transcription factor Hap1 (38). Our data suggest that proper expression of ERG genes depends on Set4 in cells grown in rich medium even under unstressed conditions, although their expression is Set4independent either with H 2 O 2 treatment or in a more depleted medium, such as synthetic complete medium (Fig.…”

Section: Discussionsupporting

confidence: 49%

“…2). In addition, these data indicate that the regulation of ERG gene expression by Set4 is not limited to hypoxia (38), and ERG genes show differential expression in set4⌬ even in aerobic conditions before hypoxic treatment when cells are grown in rich medium.…”

Section: Discussionmentioning

confidence: 76%

“…6B), suggesting that whereas regulation of ERG genes by Set4 occurs in unstressed cells, its role in gene expression appears to depend on the composition of the growth medium. As elaborated under "Discussion," this suggests a context-dependent role for Set4 in repression of ergosterol biosynthetic genes (38).…”

Section: Regulation Of Ergosterol Biosynthetic Genes By Set4 Depends mentioning

confidence: 86%

“…Ergosterol biosynthetic genes are largely down-regulated in the presence of oxidative stress (37), likely as a means to protect cells by altering membrane permeability. A recent report showed that Set4 maintains repression of ergosterol biosynthetic (ERG) genes during hypoxia (38). To test whether ERG genes are regulated by Set4 during oxidative stress, potentially as a mechanism to promote cell survival, we analyzed the expression of a subset of ERG genes in WT and set4⌬ cells following H 2 O 2 treatment.…”

Section: Regulation Of Ergosterol Biosynthetic Genes By Set4 Depends mentioning

confidence: 99%

See 4 more Smart Citations

Set4 is a chromatin-associated protein, promotes survival during oxidative stress, and regulates stress response genes in yeast

Tran

Jethmalani

Jaiswal

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

The Set4 protein in the yeast contains both a PHD finger and a SET domain, a common signature of chromatin-associated proteins, and shares sequence homology with the yeast protein Set3, the fly protein UpSET, and the human protein mixed-lineage leukemia 5 (MLL5). However, the biological role for Set4 and its potential function in chromatin regulation has not been well defined. Here, we analyzed yeast cell phenotypes associated with loss of Set4 or its overexpression, which revealed that Set4 protects against oxidative stress induced by hydrogen peroxide. Gene expression analysis indicated that Set4 promotes the activation of stress response genes in the presence of oxidative insults. Using ChIP analysis and other biochemical assays, we also found that Set4 interacts with chromatin and directly localizes to stress response genes upon oxidative stress. However, recombinant Set4 did not show detectable methyltransferase activity on histones. Our findings also suggest that Set4 abundance in the cell is balanced under normal and stress conditions to promote survival. Overall, these results suggest a model in which Set4 is a stress-responsive, chromatin-associated protein that activates gene expression programs required for cellular protection against oxidative stress. This work advances our understanding of mechanisms that protect cells during oxidative stress and further defines the role of the Set3-Set4 subfamily of SET domain-containing proteins in controlling gene expression in response to adverse environmental conditions.

show abstract

Section: Set4 Protects Cells During Oxidative Stresscontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 76%

Section: Regulation Of Ergosterol Biosynthetic Genes By Set4 Depends mentioning

confidence: 86%

Section: Regulation Of Ergosterol Biosynthetic Genes By Set4 Depends mentioning

confidence: 99%

See 3 more Smart Citations

Set4 is a chromatin-associated protein, promotes survival during oxidative stress, and regulates stress response genes in yeast

Tran

Jethmalani

Jaiswal

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

Adaptive local false discovery rate procedures for highly spiky data and their application RNA sequencing data of yeast SET4 deletion mutants

et al. 2021

View full text Add to dashboard Cite

show abstract

Genetic interaction between glyoxylate pathway regulator UCC1 and La‐motif‐encoding SRO9 regulates stress response and growth rate improvement in Saccharomyces cerevisiae

Pandita

Shoket

Rakewal

et al. 2021

J Biochem & Molecular Tox

View full text Add to dashboard Cite

Nonavailability of glucose as a carbon source results in glyoxylate pathway activation, which metabolizes nonfermentable carbon for energy generation in Saccharomyces cerevisiae. Ucc1p of S. cerevisiae inhibits activation of the glyoxylate pathway by targeting Cit2p, a key glyoxylate enzyme for ubiquitin-mediated proteasomal degradation when glucose is available as a carbon source. Sro9p, a Lamotif protein involved in RNA biogenesis, interacts physically with the messenger RNA of UCC1; however, its functional relevance is yet to be discovered. This study presents binary epistatic interaction between UCC1 and SRO9, with functional implication on the growth rate, response to genotoxic stress, resistance to apoptosis, and petite mutation. Cells with ucc1Δsro9Δ, as their genetic background, exhibit alteration in morphology, improvement in growth rate, resistance to apoptosis, and petite mutation. Moreover, the study indicates a cross-link between ubiquitinproteasome system and RNA biogenesis and metabolism, with applications in industrial fermentation and screening for cancer therapeutics.

show abstract

A Novel Sterol-Signaling Pathway Governs Azole Antifungal Drug Resistance and Hypoxic Gene Repression in Saccharomyces cerevisiae

Cited by 33 publications

References 71 publications

Set4 is a chromatin-associated protein, promotes survival during oxidative stress, and regulates stress response genes in yeast

Set4 is a chromatin-associated protein, promotes survival during oxidative stress, and regulates stress response genes in yeast

Adaptive local false discovery rate procedures for highly spiky data and their application RNA sequencing data of yeast SET4 deletion mutants

Genetic interaction between glyoxylate pathway regulator UCC1 and La‐motif‐encoding SRO9 regulates stress response and growth rate improvement in Saccharomyces cerevisiae

Contact Info

Product

Resources

About