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Elucidating the Role of Aging on Topoisomerase II Beta Expression and Repair in Neurones (Ref: SF20/APP/PADGET)


Faculty of Health and Life Sciences

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Dr K Padget Applications accepted all year round Self-Funded PhD Students Only

About the Project

Neurons show high levels of metabolic activity which results in the production of high levels of oxidative stress. However this is counterbalanced by a robust repair system in these cells. The enzyme DNA topoisomerase II beta (T2B) influences repair of DNA damage by oxidative stress, thus it is a key player in maintaining genomic integrity of these cells. This process is important as many neurodegenerative diseases such as Alzheimer’s disease cause the accumulation of oxidative stress in their early stages, which if go unrepaired may lead to further aberrant neuronal cell function and death. However, several mammalian and insect studies suggest that T2B is down-regulated in aged neurons. So understanding the impact of this upon DNA repair is an important step in elucidating the effect of aging upon levels of DNA damage in these cells. Thus the focus of the project is to investigate whether down-regulation of T2B in aged neurones is correlated with decreased levels of DNA repair and decreased transcription of key genes in these processes which may be influenced by the action of T2B. In addition the mechanism of downregulation of T2B will be investigated at the epigenetic level. Cell lines models will also be used to test whether epigenetic up regulation of T2B levels can modulate repair mechanisms and transcription in neurons, to determine whether this would be a useful potential strategy for cell therapy.

Eligibility and How to Apply:
Please note eligibility requirement:
• Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non-UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above); or APEL evidence of substantial practitioner achievement.
• Appropriate IELTS score, if required.
• Applicants cannot apply for this funding if currently engaged in Doctoral study at Northumbria or elsewhere.

For further details of how to apply, entry requirements and the application form, see
https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/

Please note: Applications should include a covering letter that includes a short summary (500 words max.) of a relevant piece of research that you have previously completed and the reasons you consider yourself suited to the project. Applications that do not include the advert reference (e.g. RDF18/…) will not be considered.

Deadline for applications: 1st July for October start, or 1st December for March start
Start Date: October or March

Northumbria University takes pride in, and values, the quality and diversity of our staff. We welcome applications from all members of the community. The University holds an Athena SWAN Bronze award in recognition of our commitment to improving employment practices for the advancement of gender equality.

Please direct enquiries to Dr Kay Padget ([Email Address Removed])

Funding Notes

Please note, this is a self-funded project and does not include tuition fees or stipend; the studentship is available to Students Worldwide. Fee bands are available at https://www.northumbria.ac.uk/study-at-northumbria/fees-funding/ . A relevant fee band will be discussed at interview based on project running costs.

References

1) Effect of TDP2 on the level of TOP2-DNA complexes and SUMOylated TOP2-DNA complexes. Lee KC, Swan R, Sondka Z, Padget K, Cowell I & Austin CA. (2018) Int J Mol Sci. 2018 Jul 14;19(7). pii: E2056.

2) Genome wide ChIP-seq analysis of human TOP2B occupancy in MCF7 breast cancer epithelial cells. Manville C, Smith K, Sondka Z, Rance H, Cockell S, Cowell I, Lee K, Morris N, Padget K, Jackson G, Austin CA. (2015) Biology Open 4(11): 1436-1447.

3) MRE11 facilitates the removal of human topoisomerase II complexes from genomic DNA. Lee KC, Padget K, Curtis H, Cowell IG, Moiani D, Sondka Z, Morris NJ, Jackson GH, Cockell SJ, Tainer JA, Austin CA. (2012) Biol Open. Sep 15;1 (9):863-73.

4) Model for MLL translocations in therapy-related leukemia involving topoisomerase IIβ-mediated DNA strand breaks and gene proximity. Cowell IG, Sondka Z, Smith K, Lee KC, Manville CM, Sidorczuk-Lesthuruge M, Rance HA, Padget K, Jackson GH, Adachi N, Austin CA. (2012) Proc Natl Acad Sci U S A. Jun 5;109 (23):8989-94.

5) Histone deacetylase inhibition redistributes topoisomerase IIβ from heterochromatin to euchromatin. Cowell IG, Papageorgiou N, Padget K, Watters GP, Austin CA. (2011) Nucleus. Jan-Feb;2(1):61-71.


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