Understanding the origins of oxidation in the nucleus

Description

Reactive oxygen species (ROS) have been thought to be harmful products of cellular metabolism, that can cause mutations that promote cancer or accelerate ageing.

We now know that reactive oxygen species are not always harmful. They also are highly conserved signalling molecules. They lead to post translational modifications on specific residues, such as cysteines and methionines, on specific proteins, altering the protein structure and function.

A question that remains unclear is where the location of origin of these ROS is, and how far they can travel in the crowded intracellular environment to act as signalling molecules.

There is a recent shift on how the field views the distribution and function of ROS. New proteomic platforms identified a plethora of proteins that have differentially oxidised cysteine residues, across different stress conditions, ageing or even different tissues. Work using novel tethered biosensor technologies show-cased for the first time that intracellular hotspots of hydrogen peroxide can exist, at distinct locations. Based on these, the field is now reconsidering the old views where each organelle has it own redox environment globally, to a new highly localised ROS model, where ROS can regulate highly localised signalling cascades.

The aim of this project is to assess the impact of highly localised ROS, especially within the nucleus. Our previous understanding of redox biology in the nucleus always considered that the nuclear envelop protects the DNA from reactive oxygen species originating primarily from the mitochondria, keeping the nuclear environment relatively reduced.

There is a growing body of research suggesting that nuclear proteins can be found under the control of redox signalling. These are not only transcription factors or kinases, but also components of transcription or epigenetic machineries. If misregulated, this can have a significant impact on cellular physiology and potentially contributes to ageing and disease progression.

The objectives of this project are:

• to identify sources of ROS that modulate the nuclear environment
• to map the proteins that are targets of ROS within the nucleus and study the effect they have in modulating components of the transcriptional machinery
• to understand how the levels of intranuclear ROS are controlled under physiological conditions and the impact they have on oxidation of nucleic acids

To address these questions the project will utilise a wide variety of techniques including novel tethered fluorescent biosensors, genetic screen platforms, proximity labelling assays and mass spectrometry, nucleic acid sequencing and of course classical biochemistry and cell biology techniques. The postgraduate researcher therefore will receive extensive training that will qualify them to be a well-rounded researcher. Additionally, the researcher will be further supported in growing their transferable and computational skills, as well as in attending national and international conferences and pursue their career aspirations.

The Kritsiligkou lab (www.kritsiligkou.com) is part of the Department of Biochemistry, Cell and Systems Biology and the Institute of Systems, Molecular and Integrative Biology (ISMIB) at the University of Liverpool. There is excellent access to core facilities and great support for the development of researchers in a vibrant and dynamic international environment.

This fully funded 4-year studentship, includes full tuition and bench fees and a stipend according to UKRI rates (amounting to approximately £19,500 pa, paid directly to the student in monthly instalments).  This funding is available to UK students only.  Starting date is flexible.

The application process is a two-step processes. Firstly, an application should be made with a full CV, transcripts and motivational letter, send to Dr Kritsiligkou (pari@liverpool.ac.uk). When a candidate has been selected following interview, a formal online application will be required. Deadline for applications is 31st January 2025. Applications might close earlier if a suitable candidate has been identified.

Requirements: A minimum of 2.1 degree is required in Biochemistry, Chemistry, Biological Sciences or related subjects and evidence of lab experience.