The Polymorphic PolyQ Tail Protein of the Mediator Complex, Med15, Regulates the Variable Response to Diverse Stresses.

Jennifer E.G Gallagher,Amaury Pupo,Michael C Ayers,Suk Lan Ser,Casey Nassif

doi:10.3390/ijms21051894

Jennifer E.G Gallagher, Amaury Pupo + Show 3 more

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https://doi.org/10.3390/ijms21051894

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Abstract

The Mediator is composed of multiple subunits conserved from yeast to humans and plays a central role in transcription. The tail components are not required for basal transcription but are required for responses to different stresses. While some stresses are familiar, such as heat, desiccation, and starvation, others are exotic, yet yeast can elicit a successful stress response. 4-Methylcyclohexane methanol (MCHM) is a hydrotrope that induces growth arrest in yeast. We found that a naturally occurring variation in the Med15 allele, a component of the Mediator tail, altered the stress response to many chemicals in addition to MCHM. Med15 contains two polyglutamine repeats (polyQ) of variable lengths that change the gene expression of diverse pathways. The Med15 protein existed in multiple isoforms and its stability was dependent on Ydj1, a protein chaperone. The protein level of Med15 with longer polyQ tracts was lower and turned over faster than the allele with shorter polyQ repeats. MCHM sensitivity via variation of Med15 was regulated by Snf1 in a Myc-tag-dependent manner. Tagging Med15 with Myc altered its function in response to stress. Genetic variation in transcriptional regulators magnified genetic differences in response to environmental changes. These polymorphic control genes were master variators.

Highlights

Changing the transcriptional landscape is a key step in reorganizing cellular processes in response to stress
The growth of yeast with different components of the Mediator complex being knocked out was tested in terms of the response to Methylcyclohexane methanol (MCHM) (Figure 1C)
Mutants in med5, med13, and med16 grew better in response to MCHM than the parental strain, BY4741, while the growth of the med15 mutant was inhibited after two days of growth

Summary

Introduction

Changing the transcriptional landscape is a key step in reorganizing cellular processes in response to stress. RNA polymerase II (pol II) transcription is regulated in a stress-specific manner via multiple post-translational modifications and a host of transcription factors (TFs). These transcription factors do not interact directly with pol II and general transcription factors (GTFs), together called the pre-initiation complex, but rather through a multi-protein complex called the Mediator. The Mediator itself is composed of four modules: the head, middle, tail, and kinase domains (Figure 1A). The head interacts with pol II and GTFs, while the tail interacts with specific TFs (reviewed in Verger et al [1]). A component of the Mediator tail complex, directly interacts with various transcription factors and has several known phosphorylations that may regulate its function. In yeast, Med regulates Oaf (fatty acid level sensor), Pdr (a transcription factor that regulates pleiotropic drug response), Ino

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