The Mediator kinase module and activating non-coding RNAs
Mediator is a general transcription coactivator and serves as bridge between enhancer-bound transcription factors and RNA polymerase II (Pol II). Mediator consists of four modules. One of these, the kinase module, consists of four subunits (Cdk8, Cyclin C, Med12 and Med13) and has been reported to both activate and repress transcription. Interestingly, Med12 associates with a large class of long ncRNAs, termed activating ncRNAs. Abrogating the interaction of Med12 with these ncRNAs leads to multiple developmental syndromes. Moreover, ncRNA-binding to Med12 activates the kinase Cdk8. However, how this activation is achieved, is mysterious, as is the modulation of Cdk8 activity by Med12 and Med13. Since Cdk8 is a major oncogene and contributes to chemotherapy resistance, it is essential to understand its regulation by subunits of the kinase module and bound ncRNA. To that end we investigate the Mediator kinase module in complex with ncRNA using structural biology.
Since lung and colon cancer, mental retardation and chemotherapy resistance are all linked to the interaction of activating ncRNAs with the Mediator kinase module, a deeper understanding of the interplay between Cdk8 kinase activity and activating ncRNAs might lead to novel, potent anti-cancer drugs.
Mediator and the general transcription machinery. The Mediator modules are kept in different colors, as is a gene-specific activator. Pol II is in brown, the general transcription factors in yellow. Cis-regulatory non-coding RNA is in cyan. Chromatin looping brings the ncRNA promoter in proximity to its target gene (adopted from Larivière et al., 2012).