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The role of DNA polymerases in aging of the mitochondrial genome


Project Description

Aims and hypothesis

Mitochondrially targeted DNA polymerases may exert positive or negative effects on mtDNA integrity, depending on whether in a normal or misregulated context. We will assess if these DNA polymerases influence the progression of mitochondrial DNA integrity and aging, and hence life- and healthspan.

Methodology and innovations

We will assess DNA polymerase localisation to mitochondria using CRISPR knockout//knockin/mutagenesis strategies in both human cells and C. elegans, using high-resolution fluorescence microscopy and biochemical cellular fractionation approaches. Effects of targeted DNA polymerases on mtDNA integrity and mitochondrial physiology will be assessed using next-generation sequencing and Seahorse metabolic analysis. The C. elegans model system will allow effects of DNA polymerase modulation on whole-organism phenotypes to be assessed (e.g. lifespan). Furthermore, in vitro biochemical analyses will assess the importance of the targeted DNA polymerases in repairing mtDNA lesions and DNA strand breakage. This will help determine if they can differentially influence acquisition of mtDNA point mutation versus deletions, and if their presence is beneficial or damaging.

Applications

Applicants must apply using the online form on the University Alliance website at https://unialliance.ac.uk/dta/cofund/how-to-apply/. Full details of the programme, eligibility details and a list of available research projects can be seen at https://unialliance.ac.uk/dta/cofund/

The final deadline for application is 12 April 2019.

Funding Notes

DTA3/COFUND participants will be employed for 36 months with a minimum salary of (approximately) £20,989 per annum. Tuition fees will waived for DTA3/COFUND participants who will also be able to access an annual DTA elective bursary to enable attendance at DTA training events and interact with colleagues across the Doctoral Training Alliance(s).
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 801604.

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