Final Report Summary - TRANSIT (Mechanism of Regulated Transcription Initiation)
The regulation of gene transcription governs eukaryotic cell growth and differentiation. Despite its importance, transcription regulation is not understood at a mechanistic level. Regulation occurs mainly during initiation, when the enzyme RNA polymerase II (Pol II) assembles with ~50 polypeptides on promoter DNA. Regulatory signals are transmitted via the Mediator coactivator complex, the structure and mechanism of which remain unclear. During this research project we could solve the structure of central complexes required for gene transcription and gene regulation and obtain a first movie that shows how transcription of a gene commences. In particular, we reported the crystal structure of the complex of RNA polymerase II with the transcription initiation factor TFIIB, the DNA template, and the RNA transcript. This structure showed how TFIIB helps the polymerase to detect the start site of transcription and how it activates RNA synthesis at the enzyme catalytic site. Second, we were able to solve the structure of the essential, gene-regulatory head module of the Mediator complex, providing a starting point for a mechanistic analysis of gene regulation. Finally, we established a new method called “dynamic transcriptome analysis”, a novel technique that measures mRNA synthesis rates and RNA degradation rates globally in cells. The method can be used to probe the mechanisms of regulated initiation by structure-based mutagenesis in vivo. These results will open new horizons for investigating the function of eukaryotic genomes, and will have a strong impact on biomedicine, since deregulated transcription underlies many diseases, including cancer.
Manfred MESSERSCHMIDT, (Head of Administration)
Record Number: 188204 / Last updated on: 2016-08-10