Molecular Biology of the Cell
The yeast cyclin C-Cdk8 kinase forms a complex with Med13p to repress the transcription of genes involved in the stress response and meiosis. In response to oxidative stress, cyclin C displays nuclear to cytoplasmic relocalization that triggers mitochondrial fission and promotes programmed cell death. In this report, we demonstrate that Med13p mediates cyclin C nuclear retention in unstressed cells. Deleting MED13 allows aberrant cytoplasmic cyclin C localization and extensive mitochondrial fragmentation. Loss of Med13p function resulted in mitochondrial dysfunction and hypersensitivity to oxidative stress-induced programmed cell death that were dependent on cyclin C. The regulatory system controlling cyclin C-Med13p interaction is complex. First, a previous study found that cyclin C phosphorylation by the stress-activated MAP kinase Slt2p is required for nuclear to cytoplasmic translocation. This study found that cyclin C-Med13p association is impaired when the Slt2p target residue is substituted with a phosphomimetic amino acid. The second step involves Med13p destruction mediated by the 26S proteasome and cyclin C-Cdk8p kinase activity. In conclusion, Med13p maintains mitochondrial structure, function, and normal oxidative stress sensitivity through cyclin C nuclear retention. Releasing cyclin C from the nucleus involves both its phosphorylation by Slt2p coupled with Med13p destruction.
Khakhina, Svetlana; Cooper, Katrina; and Strich, Randy, "Med13p Prevents Mitochondrial Fission and Programmed Cell Death in Yeast Through Nuclear Retention of Cyclin C" (2014). School of Osteopathic Medicine Faculty Scholarship. 53.
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Khakhina S, Cooper KF, Strich R. Med13p prevents mitochondrial fission and programmed cell death in yeast through nuclear retention of cyclin C. Mol Biol Cell. 2014 Sep 15;25(18):2807-16. Epub 2014 Jul 23. doi: 10.1091/mbc.E14-05-0953. PMID: 25057017. PMCID: PMC4161515.