Investigating the mechanisms of Mitochondrial DNA Repair (Mito-DR)

Applications are invited for a fully-funded three-year PhD to commence in October 2023. 

The PhD will be based in the Faculty of Science and Health, and will be supervised by Dr Robert Baldock, Dr Rhiannon McGeehan and Dr David Rusling. 

Candidates applying for this project may be eligible to compete for one of a small number of bursaries available. Successful applicants will receive a bursary to cover tuition fees at the UK/EU rate for three years and a stipend in line with the UKRI rate (£17,668 for 2022/23). Bursary recipients will also receive a £1,500 p.a. for project costs/consumables. 

Mitochondrial dysfunction has a proven role in several heritable disorders, neurodegenerative disorders, chronic fatigue syndromes, and cancers. Each cell contains hundreds to thousands of copies of the mitochondrial genome (mtDNA) – a 16.5Kb circularized DNA fragment containing 37 genes critical for mitochondrial and associated cellular functions. MtDNA mutational burden and profiles could be contributing to this mitochondrial dysfunction (Lloyd et al., 2015). In contrast to the nuclear genome, it remains unclear which DNA repair mechanisms protect the mtDNA from acquiring damage despite the high-mutagenic burden associated with cellular respiration and reactive oxygen species (ROS). 

This project aims to: 1. Uncover the mechanisms protecting mtDNA, 2. Examine the mutagenic consequences of repair deficiency at both the mtDNA, mitochondrial and cellular level and 3. Develop new nucleic acid-based nanotechnologies to aid direct detection of damaged mtDNA bases.

The PhD candidate will investigate the contribution of previously identified mtDNA repair factors (Allkanjari & Baldock., 2021) on mitochondrial function by downregulating/knocking-out these candidates in osteosarcoma and glioblastoma cells and examining them using several techniques including flow cytometry, qPCR and an array of molecular biology techniques. 

Nanopore sequencing will be used to examine the mutational burden and distinct profiles of mtDNA in cells lacking the candidate DNA repair pathways using newly established in-house sequencing pipelines. Finally, triplex-forming oligonucleotides will be used to establish novel methods to directly detect damaged bases in vitro (Rusling, 2021). 

The candidate will be supported to develop a range of subject specific, technical and transferable proficiencies throughout their study including but not limited to cell culture, bioinformatics, in vitro assay development as well as presentation and writing skills required to succeed as a future researcher.  

References:

• Allkanjari, K. and R.A. Baldock, Beyond base excision repair: an evolving picture of mitochondrial DNA repair. Bioscience Reports, 2021. 41(10): p. BSR20211320.
• Chandrasekaran, A.R. and D.A. Rusling, Triplex-forming oligonucleotides: a third strand for DNA nanotechnology. Nucleic Acids Research, 2018. 46(3): p. 1021-1037.
• Rusling, D.A., Triplex-forming properties and enzymatic incorporation of a base-modified nucleotide capable of duplex DNA recognition at neutral pH. Nucleic Acids Research, 2021. 49(13): p. 7256-7266.
• Lloyd, R.E., et al., Identification and functional prediction of mitochondrial complex III and IV mutations associated with glioblastoma. Neuro Oncol, 2015. 17(7): p. 942-52.

How to apply

We’d encourage you to contact Dr Robert Baldock (Robert.Baldock@port.ac.uk) to discuss your interest before you apply, quoting the project code.

When you are ready to apply, you can use our online application form. Make sure you submit a personal statement, proof of your degrees and grades, details of two referees, proof of your English language proficiency and an up-to-date CV.  Our ‘How to Apply’ page offers further guidance on the PhD application process.

If you want to be considered for this funded PhD opportunity you must quote project code PHBM7820423 when applying.