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Heavy metal exposure and p53 function


   Department of Biosciences

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  Dr Patricia Muller, Prof J Lunec, Dr R Clark  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

Durham United Kingdom Biochemistry Cancer Biology Cell Biology Developmental Biology Environmental Biology Molecular Biology Organic Chemistry Structural Biology

About the Project

p53 is a protein that decides whether cells live or die in response to DNA damage. This function is pivotal in a range of processes such as ageing. Heavy metals can unfold p53 and prevent it from functioning as a transcription factor. Heavy metals are found in (e-)cigarette smoke, urban dust, industrial waste, soil and a variety of other sources. Exposure to heavy metals shortens the lifespan of organisms. Interestingly, loss of p53 promotes tumour formation and decreases the lifespan of organisms.

In this program we will investigate if metal-induced loss of WT p53 expression can underlie shortened lifespan. We will investigate which metals change p53 folding and determine the consequences of this unfolding on the p53 signalling network in the response to DNA damage and on longevity. We will explore whether chelators (molecules that can catch away metals in harmless complexes) can increase the lifespan of drosophila flies. In addition, we will examine whether chelators alleviate metal inhibition of p53 and can be used in synergy with p53 activating therapies. We will explore a potential role for p53 in regulating metal homeostasis and therefore creating a feedback loop regulation.

This project will be based in three different labs in Durham and Newcastle to create a multidisciplinary PhD program combining cell biology, biochemistry, cancer biology and ageing using the strengths of each supervisor. The student will be exposed to a large variety of techniques and will benefit from state-of-the art research facilities in both sites as well as additional funding through industry.

HOW TO APPLY

Applications should be made by emailing [Email Address Removed] with:

·        a CV (including contact details of at least two academic (or other relevant) referees);

·         a covering letter – clearly stating your first choice project, and optionally 2nd ranked project, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University;

·        copies of your relevant undergraduate degree transcripts and certificates;

·        a copy of your passport (photo page).

A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE AT https://www.nld-dtp.org.uk/how-apply. Applications not meeting these criteria may be rejected.

In addition to the above items, please email a completed copy of the Additional Details Form (as a Word document) to [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

Informal enquiries may be made to [Email Address Removed]. The closing date for applications is 10th January 2022 at 5.00pm (UK time).


Funding Notes

Studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

Metal toxicity and the p53 protein : An intimate relationship Toxicol. Res., 2015, 4, 576-591
P-glycoprotein recycling by RCP to mediate chemoresistance of mutant p53 cells.
Manuscript entitled Copper-induced unfolded WT p53 exhibits mutant p53 associated gain-of-function that is under revision in Elife.
Chemical inhibition of wild-type p53-induced phosphatase 1 (WIP1/PPM1D) by GSK2830371 potentiates the sensitivity to MDM2 inhibitors in a p53-dependent manner. Molecular cancer therapeutics 2016, 15 (3), 379-391.
Rapamycin modulates tissue aging and lifespan independently of the gut microbiota in Drosophila. Scientific Reports 9(1): 2019, 7824.
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