The Shaw Prize Lecture on Life Science and Medicine 2023
13 November 2023

The Shaw Prize in Life Science and Medicine 2023 is awarded in equal shares to Patrick Cramer, Director, Department of Molecular Biology, Max Planck Institute for Multidisciplinary Sciences and President of the Max Planck Society, Germany and Eva Nogales, Distinguished Professor of Biochemistry, Biophysics and Structural Biology, Department of Molecular and Cell Biology, University of California, Berkeley, USA for pioneering structural biology that enabled visualisation, at the level of individual atoms, of the protein machines responsible for gene transcription, one of life's fundamental processes. They revealed the mechanism underlying many steps in gene transcription, how proper gene transcription promotes health, and how dysregulation causes disease.

The Central Dogma, a theory put forward in 1958 by Francis Crick, is the fundamental concept of life. Three crucial molecules are involved: DNA houses an organism's genetic blueprint. The DNA genome contains the information required to produce all of an organism's proteins. Proteins endow cells, tissues, and organisms with their forms and capabilities. Messenger RNA (mRNA) is the intermediate molecule that links DNA to proteins. Particular DNA instructions are converted into individual mRNA molecules to produce specific proteins by a process called gene transcription. Crucially, transcription of specific genes must occur at the correct times and in the correct cellular locations so that the subsets of proteins required for function are only produced when and where they are needed. The gene transcription process has four steps: 1. Initiation; 2. Pausing/ Promoter Clearance; 3. Elongation; 4. Termination. This year's Shaw Prize recipients, Eva Nogales and Patrick Cramer, pioneered structural biology approaches to enable visualisation, at the level of the individual atoms, of the protein machines responsible for gene transcription. They revealed the molecular mechanism underlying many steps in gene transcription, and the importance of proper gene transcription to promote health and prevent disease.

Visualising biology at the atomic level requires determining the structures of the tiny but highly complicated machines that catalyse life processes. Two major approaches are used: x-ray crystallography and cryo-electron microscopy. Eva Nogales pioneered cryo-electron microscopy to transform our understanding of the earliest steps in human gene transcription by focusing her efforts on the core transcription pre-initiation complex (PIC) and TFIID, a highly flexible complex comprising 14-proteins that recognizes DNA sequences marking the beginning of a gene and then recruits the rest of PIC components. The core PIC includes RNA Polymerase II and a number of general transcription factors that assemble around the transcription start site and that add up to about 30 proteins required for the launch of the gene transcription process. What is remarkable is that the TFIID and the PIC complex are scarce, fragile, and extremely flexible, all of which made the structures Nogales captured a Herculean accomplishment. Nogales revealed, for the first time, how TFIID rearranges as it binds promoter DNA and liberates TBP to initiate PIC assembly, the sequential steps of that assembly, how within the core PIC the RNA Polymerase II engages DNA, and how another large complex, TFIIH, opens the DNA double helix and brings the transcription start site into the active site of the polymerase. Nogales work led to a model of how coupling occurs between PIC states to allow transcription initiation. Patrick Cramer used x-ray crystallography and cryo-electron microscopy to determine many breathtaking structures capturing the sequential steps of gene transcription. Cramer's array of structures includes the full PIC, a 46 protein machine that contains crucial players called Mediator and TFIIH. Cramer also solved structures of RNA polymerase II after it initiates synthesis of an mRNA messenger. These structures include the paused elongation complex, the elongation complex in action, the elongation complex together with the nucleosome (nucleosomes are proteins with DNA wrapped around them and the elongation complex must clear them to proceed), the elongation complex with the nucleosome and remodeling factors, and the elongation complex with the pre-mRNA splicing complex (the splicing complex stitches mRNAs together following elongation). Combined, Cramer's extraordinary structures provide the world's first "movie" of gene transcription.

Nogales' and Cramer's landmark discoveries drove a paradigm shift in our understanding of one of life's most central processes: gene transcription. They showed how transcription can initiate and proceed, and how transcription is regulated to enable cells to differentiate so that organisms can properly develop and function.

LKS Faculty of Medicine, The University of Hong Kong

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