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

Int J Mol Sci. 2020 Mar 10;21(5):1894. doi: 10.3390/ijms21051894.

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.

Keywords: MCHM; Med15; Mediator; Myc tag; Snf1; hydrotrope; inorganic phosphate; intrinsically disordered regions; master variator; polyQ; protein chaperone; stress; transcription factors; yeast.

MeSH terms

  • Cyclohexanes / pharmacology*
  • Gene Expression Regulation, Fungal / drug effects
  • HSP40 Heat-Shock Proteins / metabolism
  • Mediator Complex / chemistry
  • Mediator Complex / genetics*
  • Mediator Complex / metabolism*
  • Mutation
  • Peptides
  • Protein Stability
  • Protein-Serine-Threonine Kinases / metabolism
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / growth & development*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Stress, Physiological

Substances

  • Cyclohexanes
  • GAL11 protein, S cerevisiae
  • HSP40 Heat-Shock Proteins
  • Mediator Complex
  • Peptides
  • Saccharomyces cerevisiae Proteins
  • YDJ1 protein, S cerevisiae
  • 4-methylcyclohexanemethanol
  • polyglutamine
  • SNF1-related protein kinases
  • Protein-Serine-Threonine Kinases