Every time a bacterium or human cell reads a gene to make a protein, it must coordinate two separate machines—one that copies DNA into RNA and another that builds the protein—or, in human cells, one that cuts the RNA before the protein is made. Scientists have known these steps are linked, but the molecular handshake between them has been invisible. This project builds the first lab-based systems that let researchers watch those interactions happen in real time, using purified components from bacteria and human cells. The team will use these systems to map exactly how the copying machine (RNA polymerase) talks to the protein-building ribosome in bacteria, and how it coordinates with the RNA-snipping spliceosome in human cells. They will also use advanced imaging (cryo-electron microscopy) to capture the three-dimensional structures of these coupled complexes. This is fundamental science: it asks how a core life process works at the atomic level. If successful, it could reveal new targets for antibiotics that jam bacterial transcription-translation coupling without harming human cells, and explain why errors in transcription-splicing coupling lead to developmental disorders and cancers.
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The first two steps of gene expression are tightly coupled in both bacteria and eukaryotes, which largely determines outcomes of gene expression. Transcription-translation coupling in bacteria is essential for viability and virulence. Transcription-splicing coupling in eukaryotes is critical for development and differentiation, and its malfunction may lead to disease. However, little is known about the molecular details of these mechanisms, mainly due to the absence of tractable experimental systems. We developed a unique in vitro transcription-translation coupled system, which we will use to investigate interactions of RNA polymerase with ribosome, how transcription regulates initiation of translation, and how ribosome controls RNA polymerase activities, transcription pausing and resolves transcription events that compromise genomic integrity. By using the first in vitro transcription-splicing coupled system, we will study direct interactions of RNA polymerase II with spliceosome ribonucleoprotein particles, how transcription elongation regulates assembly of the spliceosome and alternative splicing, and regulation of elongation by spliceosomal complexes, which is critical for splicing efficiency. In vitro programme will be complemented by new NGS-based techniques and CryoEM analysis of transcription-translation and transcription-splicing coupled complexes. The results will enrich our understanding of basic molecular processes that underpin many human diseases, and may provide new targets for antibiotics.
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