Main Supervisor: Dr. Richard Chahwan, Wellcome-Biosciences, University of Exeter
Co-Supervisor: Dr. Nicholas Harmer, Wellcome-Biosciences, University of ExeterÂ
Humans and other mammals are required to strike a fine balance between maintaining DNA integrity and mutating their immunoglobulin gene to generate immune diversity. Paradoxically, both processes require the involvement of the DNA damage response (DDR), which safeguards our bodies from tumorigenesis and immunodeficiency. Chromatin modifications have been established to play an important role in DDR. We and others have recently shown that histone ubiquitination is important for both the maintenance of genomic stability and the mitigation of the Riddle Syndrome immunodeficiency â harbouring a defective RNF168 ubiquitin ligase protein. We have now conducted further analyses in collaboration with colleagues in New York and Toronto and have found that a new histone modification might offer the missing mechanistic link between the requirement for both transcription and the DDR for antibody hypermutations. The proposed project aims to elucidate the contribution of this histone mark to basic DDR, antibody diversity, tumorigenesis, and immunodeficiency in mammals.
Successful PhD candidates will be conducting this work in a vibrant research environment at the Wellcome Building â University of Exeter, with the potential to spend some time in NYC and Toronto. The proposed PhD project will rely on various computational, molecular, and cellular techniques that have been optimized in the lab. These include: next-generation sequencing, meta-analysis of ENCODE and IMMGEN databases, culture and genetic manipulation of mammalian cells, various methods to assess the efficacy of the DNA damage response, and various methods to measure the efficacy of the immune response including somatic hyermutation and class switch recombination. The project will also rely on the biochemical expertise of the Harmer lab where we aim to purify proteins from bacterial or mammalian cells under different conditions and perform in vitro binding assays and catalytic experiments. We also aim to reconstitute nucleosomes in vitro to test the binding efficiency of various proteins modules to the histone modifications of interest.
This project has been shortlisted for funding by the BBSRC South West Doctoral Training Partnership (DTP), a collaboration between the Universities of Exeter, Bristol, Bath and Rothamsted Research institute. This project is one of a number that are in competition for funding. Studentships will be awarded on the basis of merit. The four year programme is designed to provide training in cutting edge world-class bioscience and food security research, including a structured first year of tailored taught courses and the completion of two laboratory rotations before progression onto the three year PhD. In addition, following the postgraduate training policy of the BBSRC, all students will complete a three month professional internship, providing an invaluable experience of work outside of academic research. For further details about the programme please see http://www.bristol.ac.uk/swdtp/
The studentship will cover a stipend at the standard Research Council rate (Â£13,726 per annum for 2013-2014), research costs and tuition fees at the UK/EU rate for students who meet the residency requirements outlined by the BBSRC (see http://www.bbsrc.ac.uk/web/FILES/Guidelines/studentship_eligibility.pdf).
For details of eligibility and how to apply please see theÂ Apply button below.
The closing date for applications is midnight on Friday 10th January 2014. We anticipate that interviews will take place on the 10 and 11 February 2014.