Exploring transcription of a large DNA virus of importance for global food security

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The recent covid-19 pandemic has brought viruses to the forefront of public attention. Yet it is shocking how little we know about how viruses work, including the way by which their genomes are controlled in a process called transcription. The enzymes that serve as the 'gatekeepers of the genome' are called RNA polymerases, RNAP. RNAPs are molecular machines which can be likened to other machines in our daily lives such as cars. At smaller scales, cars are powered by engines that are made of small parts, and to rationalise how cars move requires knowledge about their shape and function. While this is important to understand the mechanics of the car and the process of driving, it does not provide information about traffic. Towards larger scales, many different types of vehicles share the roads and move in a coordinated fashion in a busy city guided by traffic rules. At the largest scale, cities are interconnected by a complex network that enables travel. Likewise, RNAPs are molecular machines of life that consist of many subunits that are incorporated into higher-order transcription complexes. To understand how they work, we need to determine their structure and architecture, and characterise their function under rigorously controlled conditions in vitro, in the test tube. But in vivo, in the cell, RNAPs are not alone but interact with each other and with different machines (including the ones that replicate our genomes) and this will affect the dynamics of transcription, how RNAPs are distributed and function in the context of the genome. This proposal aims to discover the maps, the mechanics, and the 'traffic rules' of a virus RNAP. A transformative, detailed yet comprehensive, understanding of RNAP transcription requires that we study the process over a range of biological scales from the atomic- via the genomic- to the cellular level, which requires a dedicated multidisciplinary and multiscalar research strategy. I have during my career directed fundamental research which has transformed the field of transcription in the Archaea using my brand of integrative multidisciplinary research philosophy. Recently my team characterised, for the first time, the inhibition of archaeal RNAP transcription in the virus-host arms race. Our collaborators Linda Dixon and Chris Netherton at the Pirbright Institute are global leaders in ASFV virology, together we are the perfect team to carry out this ground-breaking study.