PhD Research Project: Characterisation of the mechanism of HIF mediated genoprotection in zebrafsh

Location
Sheffield, United Kingdom
Salary
Competitive
Posted
Jan 10, 2019
Closes
Feb 09, 2019
Ref
97029
Contract Type
Full Time
Job Type
PhD / Doctoral

Details

Failing DNA-repair and the resulting genome instability is now recognized to be a major factor in two important diseases that are becoming more and more prevalent due to our aging population: cancer and neurodegeneration.
While studying the hypoxic signaling pathway in zebrafish we identified a surprisingly strong effect of HIF activation on the protection of cells against DNA damaging treatments. We found that embryos with a strongly activated HIF pathway survived otherwise lethal doses of irradiation and it could even protect embryos that have a mutation in certain DNA repair genes like BRCA2. These data suggest that HIF can activate as yet unknown genoprotective mechanisms
This project aims to understand and exploit this genoprotective effect of HIF, using zebrafish genetics, fluorescent protein transgenics and technologies including CRISPR and CRISPRi, to identify and characterize the pathways involved in HIF based protection against genotoxins.

Funding Notes

These Projects are competitive studentships based at the University of Sheffield funded by BBSRC covering:
(i) a tax-free stipend at the standard Research Council rate (~£14-£15K, to be confirmed for 2019) for 4 years
(ii) research costs, and
(iii) tuition fees at the UK/EU rate for 4 years.

Studentships are available to UK and EU students who meet the UK residency requirements. Students from EU countries who do not meet the residency requirements may still be eligible for a fees-only award. Further information on eligibility: http://www.whiterose-mechanisticbiology-dtp.ac.uk/wp-content/uploads/2018/06/studentshipeligibility.pdf.

Eligibility
At least a 2:1 honours degree in a relevant subject, or equivalent.

References

Vettori A, Greenald D, Wilson GK, Peron M, Facchinello N, Markham E,Sinnakaruppan M, Matthews LC, McKeating JA, Argenton F, van Eeden FJM. Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization.
Proc Natl Acad Sci U S A. 2017 Sep 12;114(37):9948-9953.

Greenald D, Jeyakani J, Pelster B, Sealy I, Mathavan S, van Eeden FJ. Genome-wide mapping of Hif-1α binding sites in zebrafish. BMC Genomics. 2015 Nov
11;16:923.

Chowdhury R, Candela-Lena JI, Chan MC, Greenald DJ, Yeoh KK, Tian YM, McDonough MA, Tumber A, Rose NR, Conejo-Garcia A, Demetriades M, Mathavan S, Kawamura A, Lee MK, van Eeden F, Pugh CW, Ratcliffe PJ, Schofield CJ. Selective small molecule probes for the hypoxia inducible factor(HIF) prolyl hydroxylases. ACS Chem Biol. 2013 Jul 19;8(7):1488-96.

Walker C, Herranz-Martin S, Karyka E, Liao C, Lewis K, Elsayed W, Lukashchuk V, Chiang SC, Ray S, Mulcahy PJ, Jurga M, Tsagakis I, Iannitti T, Chandran J, Coldicott I, De Vos KJ, Hassan MK, Higginbottom A, Shaw PJ, Hautbergue GM, Azzouz M, El-Khamisy SF. C9orf72 expansion disrupts ATM-mediated chromosomal break repair. Nat Neurosci. 2017 Sep;20(9):1225-1235.