Completed Genetics & Molecular Biology Cells, Biochemistry & Physiology

Mechanisms and Regulation of RNAP transcription

Funder Wellcome Charity-funded
Recipient organisation University College London
Funding £2.0M
Period Apr 2018 — Apr 2023

In plain English

AI plain-English summary

Every living cell depends on a single molecular machine—RNA polymerase (RNAP)—to read its genes and produce the proteins that keep it alive. This project aims to understand exactly how RNAP works, what controls it, and how viruses can hijack it. The problem is that while we know RNAP is central to gene expression, the detailed mechanics of how it starts, continues, and stops reading DNA remain poorly understood. We also know little about the proteins and RNA molecules that regulate it, or how viruses can shut it down entirely during infection. This is fundamental science. The researchers will use a combination of bespoke biochemical assays, structural biology, and genome-wide mapping to characterise RNAP’s molecular partners in living cells. They will also study how archaeal chromatin—a simpler version of human chromatin—affects RNAP movement, and how viral proteins can act as global transcription inhibitors, much like antibiotics. If successful, this work will reveal the basic operating principles of a machine that sits at the heart of all life. Deeper understanding of RNAP regulation could eventually inform the design of new antimicrobials or antiviral strategies, but the immediate goal is to answer a foundational question: how does a cell decide which genes to read, and when to stop?

View original technical description
This grant focuses on four lines of scientific enquiry converging on RNAP function 1. Characterisation of the molecular mechanisms underlying RNA polymerase and basal factors that facilitate transcription initiation, elongation and termination by using multidisciplinary approaches in vivo and in vitro. This includes using bespoke transcription assays, structure elucidation and a global characterization of the occupancy and transcriptomes. 2. Identification of novel gene-specific factors and characterization of the proteomes of transcription preinitiation- and elongation complexes in vivo. Identification and characterization of RNAP-associated proteinaceous- and RNA regulators. 3. Characterisation of the structure and function of archaeal chromatin formed by A3 and 1647 histone variants. A biophysical characterization of protein-DNA interactions and a whole-genome view of histone occupancy. Focus on the impact of chromatin on RNAP as it progresses through the transcription cycle, and the role of elongation factors to overcome the inhibitory effect of chromatin. 4. Characterisation of factors that modulate RNAP during virus-host interactions. Virus (RIP)- and host (TFS4)-encoded RNAP-binding factors function as global inhibitors of transcription and their mechanism is reminiscent of antibiotics. Using two virus libraries of we want to screen for novel RNAP-binding regulators and use them as molecular probes to dissect RNAP function.

View the original record at the funder ↗

Researchers

Finn Werner (EPMC Awardee)

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Original classification

Investigator Award in Science

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