A complex molecular switch directs stress-induced cyclin C nuclear release through SCFGrr1 mediated degradation of Med13.
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 that, with Med12 and Med13, associate with the core mediator complex of RNA polymerase II. In S. cerevisiae, oxidative stress triggers Med13 destruction, which thereafter releases cyclin C into the cytoplasm. Cytoplasmic cyclin C associates with mitochondria where it induces hyper-fragmentation 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 phospho-degron 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 that this IDR of Med13 plays a key role in controlling a molecular switch that dictates cell fate following exposure to adverse environments.
Published In/Presented At
Stieg, D. C., Willis, S. D., Ganesan, V., Ong, K. L., Scurozo, J., Song, M., & ... Cooper, K. F. (2017). A complex molecular switch directs stress-induced cyclin C nuclear release through SCFGrr1 mediated degradation of Med13. Molecular Biology Of The Cell, 1;29(3), 363-375. doi:10.1091/mbc.E17-08-0493
Medical Cell Biology | Medical Microbiology | Medical Molecular Biology | Medical Sciences | Medicine and Health Sciences | Osteopathic Medicine and Osteopathy
Department of Medicine, Department of Medicine Fellows and Residents