JAMMpacked: the ubiquitin network regulated by JAMM-type ubiquitin proteases.

Co Supervisor: Dr Aude Echalier, Departments of Biochemistry and of Cancer Studies, University of Leicester.
Initial enquires can be made by contacting Jo Morris [Email Address Removed]
Duration: 4 years

Who Can Apply?
• British nationals who have lived in the UK all their lives are eligible.
• Also eligible are non-British nationals who have settled status AND have been resident in the UK for 3 years immediately prior to the date of the start of the course.
• EU nationals who have been ordinarily resident in the UK and Islands for three years immediately prior to the date of start of the course;
• EU nationals not resident in the UK are eligible for matched funding studentships only.
see http://www2.warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application/ for further details

You will have or expect to achieve a 2:1 or First class degree or equivalent a strong interest in a research career and a desire to approach biological problems from a systems perspective.

How to apply:
These links will assist you in verifying whether you are eligible.

1. Check your eligibility here: http://www2.warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application/#Eligibility
2. Notify MIBTP of your application by completing an online notification form here: http://www2.warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application/submission/

The post-translational modification of cellular proteins with one or more moieties of the small protein modifier Ubiquitin (Ub) is implicated in all areas of cell biology. Ub can alter the activity, localisation, interactions and stability of target proteins. Conjugation with Ub is involved in virtually all cellular functions and is known to central to key processes such as protein degradation and intracellular signalling. The enzymes involved in removal of Ub-moieties from targeted proteins have received attention as potential small molecule targets for the treatment of human diseases, most notably in cancer. The hundred or so de-ubiquitinating enzymes in the human genome are represented in five classes, one of which is the metalloproteases of the JAB1/MPN+/MOV34 (JAMM) class[1]. Several of these enzymes are present in large multi-subunit complexes, such as the Cop9 Signalosome and 19S proteasome whereas others appear to be ‘stand-alone’ enzymes. The majority, but not all the enzymes in this class are able to cleave Ub-chains that are linked together via lysine-63 and generally belong to important cellular processes. This type of Ub linkage is implicated in intracellular signalling in the inflammatory response and in the DNA damage response [2, 3]. Both are pathways vital to the control and development of cancer.
In this project you will study one of the JAMM-type proteases of which we currently know very little, but that our preliminary findings suggest plays a vital role in the way mammalian cells respond to DNA damage (identified in the screen shown in Fig 1A [4]). Thus understanding the networks that this enzyme regulates may help our understanding of cancer development and treatment.
Using a combination of approaches, such as protein production and purification, biochemical characterisation, genome editing, confocal microscopy, mass spectrometry and computational approaches we aim to address the following:

• What type of ubiquitin-targets can the protease act on, and is it specific to lysine-63 linkages?
• What are the targets of the protease and what cellular functions are these involved in?
• How does the regulation of key cellular processes by this enzyme help inform our understanding of ubiquitin-networks in general?
This project is an ideal training for anyone interested in applying systems biology approaches, such as proteomics to understanding regulatory pathways in cells relevant to cancer development and treatment. It will also provide a good grounding for those interested in a career in the pharmaceutical and biotechnologies industries.
Training: In addition to the PhD project this scheme includes cutting edge training. In year 1. Quantitative skills modules. A series of bespoke Masterclasses and hands-on workshops in selected advanced research skills and technologies. Two mini-projects will be chosen in different disciplines and partner universities. A professional internship taken outside of the lab in destinations such as policy making, media, IP management, teaching and industry. In years 2-4 modules on Research Skills training, Personal Development and Industry Training are offered including an Annual Conference and Careers focus events. For further information see: http://www2.warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/trainingprogramme/