Investigating how lysine methylation controls neuronal DNA repair

 Dr M Higgs

Application Deadline: Applications accepted all year round

Details

Our genomic DNA is under constant attack from DNA damaging agents, which are a continuing threat to genomic integrity. Defective resolution of DNA damage underlies several human diseases, including neurological abnormalities and developmental disorders as well as cancer. To counteract this, multiple DNA damage response (DDR) proteins act to combat DNA damage, by detecting DNA damage, activating cell cycle checkpoints, and promoting the repair/resolution of DNA lesions. The activity of these factors in cells is controlled by a complex network of post-translational modifications (PTMs). However, the role of epigenetic PTMs in controlling the DRR is less well understood. This is especially true in neuronal cells, which rely on specialised DDR sub-pathways for repair of damage, whilst at the same time being more prone to damage as a consequence of high metabolic activity.

My group is interested in one particular PTM, lysine methylation, the enzymes that catalyse this, and how they control the DDR in neurons. Studies from our lab (amongst others) have shown that these ‘lysine methyltransferases’ play vital roles in promoting DNA repair via several DDR pathways, as well as maintaining neurological function. Indeed, cells from patients deficient in lysine methylation enzymes exhibit defects in the DDR as well as neurological diseases. However, it is unclear whether the neurological phenotypes seen in these patients arise because of defective DNA repair.

This PhD will investigate how loss of lysine methylation impacts upon the DDR in neurons and investigate the consequences for neuronal function. The project will involve a wide variety of laboratory techniques, including culture of iPSC and neuronal cells, co-immunoprecipitation, CRISPR-Cas9 and Cas12 techniques, in vitro activity and binding assays, fluorescent and visual microscopy, immunoblotting and immunofluorescence, molecular cloning, and metabolic/neuronal activity assays. These approaches will lead to a greater understanding of how lysine methylation is involved in maintaining genome stability in neurons and the implications for neurological disease.

For further information, please contact m.r.higgs@bham.ac.uk.

Person Specification:

Applicants should have a strong background in molecular and cellular biology, with experience of the following laboratory techniques: cell culture, immunofluorescence; immunoblotting and molecular cloning. Previous experience of a research lab environment and mammalian tissue culture is essential. They should be ambitious, enthusiastic and self-motivated, and hold at least an Upper Second Class Honours Degree in a relevant biological subject. If applicable, they should also be able to demonstrate proficiency in the English language with relevant scores in both reading and speaking (e.g. IELTS).

Funding Notes

Self-funded PhD students only.