Document Type

Article

Version Deposited

Published Version

Publication Date

9-15-2014

Publication Title

Molecular Biology of the Cell

DOI

10.1091/mbc.E14-05-0953

Abstract

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.

Comments

Molecular Biology of the Cell (MBoC) is an online journal published twice monthly and owned by the American Society for Cell Biology (ASCB). Unredacted accepted manuscripts are freely accessible immediately through MBoC In Press. Final published versions are freely accessible two months after publication at www.molbiolcell.org. MBoC is also available online through PubMed Central, sponsored by the U.S. National Library of Medicine.

Creative Commons License

Creative Commons Attribution-Noncommercial-Share Alike 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

Published Citation

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.

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