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Molecular characterisation of novel interactions of DNA repair proteins


Project Description

Human exposure to alkylating agents is unavoidable through both exogenous sources and endogenous formation. Some of these compounds have been shown to be toxic and carcinogenic in animal models and some are known human carcinogens. Their mode of action likely stems from the formation of specific types of DNA damage since DNA repair proteins that can eliminate this damage have been shown to provide protection against the mutagenic and carcinogenic consequences of alkylating agent exposure in vitro and in vivo. However the precise role of these repair systems in preventing human cancer is currently unclear, and there is increasing evidence of hitherto unsuspected roles of specific repair proteins There is therefore a need to fully characterise the mechanisms, crosstalk and interactions of these proteins in the processing of alkylating agent-induced DNA damage.

In this particular PhD project, the student will aim to investigate how different types of DNA damage are repaired in human cells so as to better understand how these proteins might provide protection in human populations.

The student will be integrated into an active research group and will be trained to use advanced molecular and cell biology techniques and molecular modelling, based on our previous work on orthologous genes in eukaryotes. New human cell lines will be developed via the cutting-edge technique of CRISPR-Cas9 gene-editing. These will be used in toxicological studies as well as in comprehensively assessing the diverse mutagenic consequences of the unrepaired alkylation damage via Next Generation Sequencing. There will be opportunities to present results at national and international conferences, and public engagement events.

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with experience in molecular biology or with an interest in toxicology are encouraged to apply.

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Occupational and Environmental Health.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

Fees can be found here K:\FBMH Doctoral Academy\DA Reference Library - Policy and Procedures\Fees


References

O’Connor, P.J., Alonso-Amelot, M.E., Roberts, S.A., Povey, A.C. (2019) The role of bracken fern illudanes in bracken fern-induced toxicities. Mutat. Res., doi: 10.1016/j.mrrev.2019.05.001 [Epub ahead of print]

Shangula, S., Noori, M., Ahmad, I., Margison, G.P., Liu, Y., Siahmansur, T., Soran, H, Povey AC (2019) PON1 increases cellular DNA damage by lactone substrates. Arch Toxicol., 93:2035-43.

Potjewyd, G., Day, P.J., Shangula, S., Margison, G.P., Povey, A.C. (2017) L-β-N-methylamino-l-alanine (BMAA) nitrosation generates a cytotoxic DNA damaging alkylating agent: An unexplored mechanism for neurodegenerative disease. Neurotoxicology, 59:105-9.

Alqahtani, S., Promtong, P., Oliver, A.W., He, X.T., Walker, T.D., Povey, A., Hampson, L., Hampson, I.N. (2016) Silver nanoparticles exhibit size-dependent differential toxicity and induce expression of syncytin-1 in FA-AML1 and MOLT-4 leukaemia cell lines. Mutagenesis, 31:695-702.

Dumax-Vorzet, A.F., Tate, M., Walmsley, R., Elder, R.H., Povey, A.C. (2015) Cytotoxicity and genotoxicity of urban particulate matter in mammalian cells. Mutagenesis,30:621-33.

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