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PhD Studentship - Regulation of Mitochondrial Gene Expression


Studentship

A three-year PhD studentship is available commencing in October 2018, under the supervision of Dr Michal Minczuk (Mitochondrial Genetics):

Regulation of Mitochondrial Gene Expression

The key objective of this PhD project is to study genes involved in mitochondrial (mt-) RNA metabolism, in order to understand how their dysfunction is linked to human mitochondrial pathologies.

The human mitochondrial genome (mtDNA) codes for several structural components of the oxidative phosphorylation system (OxPhos) and RNA components for intra-mitochondrial protein synthesis. Therefore, mitochondria have evolved unique and highly specialised mechanisms to express the mtDNA-encoded genes. The mitochondrial rRNAs, mRNAs and tRNAs are transcribed as polycistronic units. Following the endonucleolytic processing, individual transcripts undergo post-transcriptional maturation. Several nucleotides of mt-rRNAs are modified to facilitate mitoribosome biogenesis and function, a poly(A) tail is added to mt-mRNAs and mt-tRNAs undergo extensive post-transcriptional modifications, before being aminoacylated with a cognate amino acid. Turnover and surveillance pathways have also been described for mammalian mt-RNA [1].

Establishing how defects in these processes contribute to human mitochondrial disease constitutes a major challenge. Our recent studies have brought many important insights into the regulation of mtDNA expression. We have identified and characterised a number of novel factors, either by basic research approaches, or through the study of patients with mitochondrial disorders. Currently, we try to understand the regulation of mammalian mitochondrial gene expression focussing on the following fundamental processes:

-Polyadenylation of mitochondrial RNA [2]

-Post-transcriptional modification ("epitranscriptomics") of mitochondrial RNA [3, 4]

-Biogenesis of mitochondrial ribosome [5]

In our research, we use the following latest tools and techniques: next generation RNA sequencing (RNA-Seq) to characterise mt-RNA abundance, processing and maturation [2,3]; HITS-CLIP to study RNA-protein interactions [3]; SILAC-based proteomics, RNASeq-based ribosome profiling and CryoEM for analyses of mitochondrial translation and mitochondrial ribosome [2] (please see References below).

Funding

Funding will cover the student's stipend at the current rate of £16,000 per annum, along with University Fees for three years, subject to eligibility. The studentship is available to UK nationals and EU students who meet the UK residency requirements. Applications from ineligible candidates will not be considered.

About the MRC Mitochondrial Biology Unit

Research at the MRC Mitochondrial Biology Unit (MBU) is focussed on the involvement of mitochondria and their dysfunction in an ever-increasing range of human diseases, and even, perhaps, in the process of ageing. Our Unit has three major scientific aims:

-To understand the fundamental processes taking place in mitochondria

-To understand the involvement of these processes in human diseases

-To exploit knowledge of these fundamental processes for the development of new therapies to treat human diseases

We have eight independent research groups (see www.mrc-mbu.cam.ac.uk). Their activities are focussed on understanding the fundamental biochemical and biological processes which occur in mitochondria. Via collaborations with clinical colleagues in several countries, we are building on our fundamental knowledge to try to understand how mitochondrial dysfunction leads to human disease. In addition, we are engaged in collaborations with pharmaceutical companies, to exploit our fundamental knowledge to generate new therapies.

For further information, please contact Penny Peck: postgraduate.manager@mrc-mbu.cam.ac.uk

Applications should be made online via the University's Applicant Portal using the MRC MBU's course code (MDDN22). Details of how to apply are on: https:// www.graduate.study.cam.ac.uk/courses/directory/blmbpdbsc/apply. Applicants should hold or be about to achieve a First or Upper-Second (2.1) class degree in a relevant subject.

Please include details of your referees, including email address and phone number, one of which must be your most recent line manager.

The closing date for applications is Saturday 30th June 2018.

Please quote reference SM15459 on your application and in any correspondence about this vacancy.

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Further information