Grant: Project Grant

Cells are the basic building blocks of living organisms, and all cellular activities are encoded by genes in DNA. The genes are then "transcribed" to form RNAs that are "translated" to proteins, which in turn do most of the work in the cell. The enzymes that convert DNA to RNA in transcription are called RNA Polymerases. Cells require at least three different kinds of RNA polymerases to generate all the different types of RNA. Moreover, each of the RNA Polymerases requires other proteins to direct them to the correct places in the DNA. One of these proteins is called TBP. Found in virtually all organisms, TBP is an essential protein, and without it, organisms do not survive. Importantly, decades of research have shown that TBP is required for transcription by all three RNA Polymerases, providing further testament to its central role in transcription. Despite what we know about TBP, we found that TBP is not required for transcription of protein-coding genes in mouse embryonic stem cells. This finding stands in contrast to one of the main dogmas of molecular biology. If transcription can occur without TBP, what do we really know about how genes are transcribed? Our research project will address this question for each of the three main RNA Polymerases in mouse embryonic stem cells. We will tackle this question through different approaches, combining molecular biology, advanced DNA sequencing, and live- cell microscopy. This multi-pronged approach will allow us to redefine the central role of TBP and generate new insights into how genes are transcribed. Since transcription underlies how cells function, and therefore how organisms develop, the results from this study will have a broad impact in cell and developmental biology. Importantly, many diseases arise from transcription errors, and by understanding precisely how transcription works, we can better identify problems and find solutions when things go wrong during disease.