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The role of proteosome-mediated proteolysis in modulating potentially harmful transcription factor activity in Saccharomyces cerevisiae.

Bonzanni N, Zhang N, Oliver SG, Fisher J - Bioinformatics (2011)

Bottom Line: Particularly, controlling the abundance of proteins that may have detrimental effects on cell growth is crucial for rapid recovery from stress-induced quiescence.Additional bioinformatics analyses show that potentially toxic transcriptional regulators have a significantly lower protein half-life, a higher fraction of unstructured regions and more potential PEST motifs than the non-detrimental ones.Our combined results suggest that proteasome-mediated proteolysis of potentially toxic transcription factors tightly modulates the stress response in yeast. jasmin.fisher@microsoft.com

View Article: PubMed Central - PubMed

Affiliation: Centre for Integrative Bioinformatics VU, VU University Amsterdam, De Boelelaan 1081a, 1081 HV Amsterdam, The Netherlands.

ABSTRACT

Motivation: The appropriate modulation of the stress response to variable environmental conditions is necessary to maintain sustained viability in Saccharomyces cerevisiae. Particularly, controlling the abundance of proteins that may have detrimental effects on cell growth is crucial for rapid recovery from stress-induced quiescence.

Results: Prompted by qualitative modeling of the nutrient starvation response in yeast, we investigated in vivo the effect of proteolysis after nutrient starvation showing that, for the Gis1 transcription factor at least, proteasome-mediated control is crucial for a rapid return to growth. Additional bioinformatics analyses show that potentially toxic transcriptional regulators have a significantly lower protein half-life, a higher fraction of unstructured regions and more potential PEST motifs than the non-detrimental ones. Furthermore, inhibiting proteasome activity tends to increase the expression of genes induced during the Environmental Stress Response more than those in the rest of the genome. Our combined results suggest that proteasome-mediated proteolysis of potentially toxic transcription factors tightly modulates the stress response in yeast.

Contact: jasmin.fisher@microsoft.com

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Comparison between toxic and non-toxic regulators. (A) The half-lives of toxic regulators (red) are significantly lower (P=5.54×10−3; Wilcoxon test) than those of non-toxic ones (blue), while (B) the median half-life of the transcripts of toxic regulators is not significantly different from that of the non-toxic ones (P=0.256; Wilcoxon test). (C) The fraction of amino acids predicted to form unstructured regions is significantly higher in toxic than in non-toxic proteins (P=2.48×10−4; Wilcoxon test). (D) After 120 min of proteasome inhibition by MG132, transcription rates of UES genes (P=8.26×10−05; Wilcoxon test) and ESR induced genes (P<2.2×10−16; Wilcoxon test) tend to be higher than those for the rest of the genome.
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Figure 4: Comparison between toxic and non-toxic regulators. (A) The half-lives of toxic regulators (red) are significantly lower (P=5.54×10−3; Wilcoxon test) than those of non-toxic ones (blue), while (B) the median half-life of the transcripts of toxic regulators is not significantly different from that of the non-toxic ones (P=0.256; Wilcoxon test). (C) The fraction of amino acids predicted to form unstructured regions is significantly higher in toxic than in non-toxic proteins (P=2.48×10−4; Wilcoxon test). (D) After 120 min of proteasome inhibition by MG132, transcription rates of UES genes (P=8.26×10−05; Wilcoxon test) and ESR induced genes (P<2.2×10−16; Wilcoxon test) tend to be higher than those for the rest of the genome.

Mentions: With our first analysis, we assessed whether the protein half-lives of toxic regulators are shorter than those of non-toxic regulators, using the protein half-life measurements of Belle et al. (2006). Since the measurements are not normally distributed (P<10−15; Shapiro–Wilk test), we computed the Wilcoxon rank sum test under the hypothesis that the median difference between the two measurement sets is zero and the alternative hypothesis that the median half-life of the toxic transcription factors is less than that of the non-toxic ones. The hypothesis has been discarded with the statistically significant value of P=5.54×10−3 (Fig. 4A). Note that it was not possible to find measurements for all the proteins in the two sets. We also analyzed the mRNA half-life data (Wang et al., 2002) for the transcripts of the toxic and the non-toxic TFs and found no significant difference between the two (P=0.256; Wilcoxon test), supporting the hypothesis that a significant portion of the control over the toxic TFs is exerted post-transcriptionally (Fig. 4B).Fig. 4.


The role of proteosome-mediated proteolysis in modulating potentially harmful transcription factor activity in Saccharomyces cerevisiae.

Bonzanni N, Zhang N, Oliver SG, Fisher J - Bioinformatics (2011)

Comparison between toxic and non-toxic regulators. (A) The half-lives of toxic regulators (red) are significantly lower (P=5.54×10−3; Wilcoxon test) than those of non-toxic ones (blue), while (B) the median half-life of the transcripts of toxic regulators is not significantly different from that of the non-toxic ones (P=0.256; Wilcoxon test). (C) The fraction of amino acids predicted to form unstructured regions is significantly higher in toxic than in non-toxic proteins (P=2.48×10−4; Wilcoxon test). (D) After 120 min of proteasome inhibition by MG132, transcription rates of UES genes (P=8.26×10−05; Wilcoxon test) and ESR induced genes (P<2.2×10−16; Wilcoxon test) tend to be higher than those for the rest of the genome.
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Figure 4: Comparison between toxic and non-toxic regulators. (A) The half-lives of toxic regulators (red) are significantly lower (P=5.54×10−3; Wilcoxon test) than those of non-toxic ones (blue), while (B) the median half-life of the transcripts of toxic regulators is not significantly different from that of the non-toxic ones (P=0.256; Wilcoxon test). (C) The fraction of amino acids predicted to form unstructured regions is significantly higher in toxic than in non-toxic proteins (P=2.48×10−4; Wilcoxon test). (D) After 120 min of proteasome inhibition by MG132, transcription rates of UES genes (P=8.26×10−05; Wilcoxon test) and ESR induced genes (P<2.2×10−16; Wilcoxon test) tend to be higher than those for the rest of the genome.
Mentions: With our first analysis, we assessed whether the protein half-lives of toxic regulators are shorter than those of non-toxic regulators, using the protein half-life measurements of Belle et al. (2006). Since the measurements are not normally distributed (P<10−15; Shapiro–Wilk test), we computed the Wilcoxon rank sum test under the hypothesis that the median difference between the two measurement sets is zero and the alternative hypothesis that the median half-life of the toxic transcription factors is less than that of the non-toxic ones. The hypothesis has been discarded with the statistically significant value of P=5.54×10−3 (Fig. 4A). Note that it was not possible to find measurements for all the proteins in the two sets. We also analyzed the mRNA half-life data (Wang et al., 2002) for the transcripts of the toxic and the non-toxic TFs and found no significant difference between the two (P=0.256; Wilcoxon test), supporting the hypothesis that a significant portion of the control over the toxic TFs is exerted post-transcriptionally (Fig. 4B).Fig. 4.

Bottom Line: Particularly, controlling the abundance of proteins that may have detrimental effects on cell growth is crucial for rapid recovery from stress-induced quiescence.Additional bioinformatics analyses show that potentially toxic transcriptional regulators have a significantly lower protein half-life, a higher fraction of unstructured regions and more potential PEST motifs than the non-detrimental ones.Our combined results suggest that proteasome-mediated proteolysis of potentially toxic transcription factors tightly modulates the stress response in yeast. jasmin.fisher@microsoft.com

View Article: PubMed Central - PubMed

Affiliation: Centre for Integrative Bioinformatics VU, VU University Amsterdam, De Boelelaan 1081a, 1081 HV Amsterdam, The Netherlands.

ABSTRACT

Motivation: The appropriate modulation of the stress response to variable environmental conditions is necessary to maintain sustained viability in Saccharomyces cerevisiae. Particularly, controlling the abundance of proteins that may have detrimental effects on cell growth is crucial for rapid recovery from stress-induced quiescence.

Results: Prompted by qualitative modeling of the nutrient starvation response in yeast, we investigated in vivo the effect of proteolysis after nutrient starvation showing that, for the Gis1 transcription factor at least, proteasome-mediated control is crucial for a rapid return to growth. Additional bioinformatics analyses show that potentially toxic transcriptional regulators have a significantly lower protein half-life, a higher fraction of unstructured regions and more potential PEST motifs than the non-detrimental ones. Furthermore, inhibiting proteasome activity tends to increase the expression of genes induced during the Environmental Stress Response more than those in the rest of the genome. Our combined results suggest that proteasome-mediated proteolysis of potentially toxic transcription factors tightly modulates the stress response in yeast.

Contact: jasmin.fisher@microsoft.com

Show MeSH
Related in: MedlinePlus