A complex molecular switch directs stress-induced cyclin C nuclear release through SCFGrr1-mediated degradation of Med13

David C. Stieg, Stephen D. Willis, Vidyaramanan Ganesan, Kai Li Ong, Joseph Scuorzo, Mia Song, Julianne Grose, Randy Strich, Katrina F. Cooper

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

In response to oxidative stress, cells decide whether to mount a survival or cell death response. The conserved cyclin C and its kinase partner Cdk8 play a key role in this decision. Both are members of the Cdk8 kinase module, which, with Med12 and Med13, associate with the core mediator complex of RNA polymerase II. In Saccharomyces cerevisiae, oxidative stress triggers Med13 destruction, which thereafter releases cyclin C into the cytoplasm. Cytoplasmic cyclin C associates with mitochondria, where it induces hyperfragmentation and regulated cell death. In this report, we show that residues 742-844 of Med13's 600-amino acid intrinsic disordered region (IDR) both directs cyclin C-Cdk8 association and serves as the degron that mediates ubiquitin ligase SCFGrr1-dependent destruction of Med13 following oxidative stress. Here, cyclin C-Cdk8 phosphorylation of Med13 most likely primes the phosphodegron for destruction. Next, pro-oxidant stimulation of the cell wall integrity pathway MAP kinase Slt2 initially phosphorylates cyclin C to trigger its release from Med13. Thereafter, Med13 itself is modified by Slt2 to stimulate SCFGrr1-mediated destruction. Taken together, these results support a model in which this IDR of Med13 plays a key role in controlling a molecular switch that dictates cell fate following exposure to adverse environments.

Original languageEnglish (US)
Pages (from-to)363-375
Number of pages13
JournalMolecular biology of the cell
Volume29
Issue number3
DOIs
StatePublished - Feb 1 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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