PhD Opportunity – The NF-ĸB transcription factor

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Project outline: The NF-ĸB transcription factor is a master regulator of the immune response and plays a critical role in inflammatory disease by mediating the expression of pro-inflammatory factors. The NF-ĸB-directed transcription of genes that promote cell survival and proliferation also implicates it as an important factor in cancers and neurodegenerative disorders. The key roles for NF-ĸB in the pathogenesis of these and other diseases have established it as an important therapeutic target, which to date remains unharnessed. Previous strategies focussed on inhibiting the IKK kinases, critical activators of NF-ĸB, have failed to make clinical impact due to severe side-effects, and so new approaches to targeting NF-ĸB for therapeutic benefit are required. This project aims to exploit the regulation of NF-ĸB by the ubiquitin proteasome system in order to inhibit NF-ĸB mediated inflammatory responses. The ubiquitin-triggered proteasomal degradation of NF-ĸB is a major limiting factor in the expression of pro-inflammatory genes. We have previously identified the deubiquitinase USP7 as a key regulator of NF-ĸB transcriptional activity by reversing NF-ĸB ubiquitination and preventing its proteasomal degradation. We have extended these initial findings to identify a distinct NF-ĸB binding site in USP7 that selectively mediates the interaction of USP7 with NF-ĸB. We hypothesise that this binding site could be targeted to selectively inhibit NF-ĸB-directed inflammatory responses by promoting its ubiquitination and degradation. This project is a structure-function based study of the USP7 and NF-ĸB interface that will define the NF-ĸB binding site and the functional impact of its disruption. The results will facilitate the rational structure-led design of substrate-selective inhibitors of USP7 to inhibit NF-kB mediated inflammatory responses.

Summary aim: This project will investigate the potential to inhibit inflammation by inhibiting the deubiquitination of NF-κB by USP7.

Techniques to be used: CRISPR/Cas9 gene editing, molecular biology (including site directed mutagenesis), protein purification and X- ray crystallography, proteomics and transcriptomics.

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