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Molecular Dynamic modelling of DNA repair sites


   Cardiff School of Biosciences

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  Dr Georgina Menzies  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

DNA structure and sequence context plays an important role in the rate of DNA repair. The influence of small changes in both nearest and further neighbouring bases have been studied, however, the interactions between DNA-carcinogens and these base contexts are largely unknown. There are at least sixty carcinogens present in tobacco smoke many of which are thought to cause cancer by the induction of DNA damage. The damage induced by many of these carcinogens may impact upon DNA repair protein’s ability to bind to DNA or carry out repair.

We have shown, previously, that DNA sequences in certain contexts are structurally different to those which are not hot spot mutation sites for lung cancer. (10.1186/s13065-021-00777- 8) (10.1093/nar/gkv910). We have also recently studied some of these structures in a DNA repair context with a Protein-DNA simulation. Here we found difference in binding between the protein and DNA between two known adduct sites – one a cancer hotspot and the other a non-mutating site. We were able to correlate differences with the DNA protein’s ability to carry out its function and are in the process of preparing the manuscript for this.

In this PhD we will look to see if we can find statistical differences, in first a DNA context and then a DNA-Protein context, between high and low numbers from the mutational signatures found in tobacco mutational signatures in the COSMIC database (Figure 1). Some of our published methods will be used in this project to study all possible DNA sequence contexts (three letter DNA sequences to start with expanding to further effects). We will then correlate those structures back to cancer sequences in genes from the COSMIC database.

There will also be an opportunity for the student expand upon the project by choosing alternative DNA adducts and study further DNA repair proteins as the project progresses.

Techniques:

The student will use various in silico techniques to study the protein and DNA structure and elude functional information. These will include - Molecular Dynamics, homology modelling, molecular docking and various analysis techniques including energy binding calculations.

Supervisors:

Dr Georgina Menzies and Dr Jamie Platts

This studentship is expected to start in October 2022.


Funding Notes

Funding covers Home UK student fees, stipend and consumables.
EU and International Students may apply but will need to cover the difference between Home UK and International fees

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