Determining the susceptibility of nucleic acids to damage as a function of structure

This project is to examine the relationship between the structure of nucleic acids (DNA and RNA) and their susceptibility to damage. Chemical modification of nucleic acids can have a profound effect on cell viability and function. DNA can be damaged by a number of chemical species including reactive oxygen species (ROS). This causes mutation within the genome which can lead to a number of different diseases, including cancer, and is a hallmark of several neurodegenerative diseases including frontotemporal dementia. In Alzheimer’s disease, metals such as iron can increase the amount of damage suffered by nucleic acids through Fenton chemistry. However, DNA and RNA can adopt a wide variety of structures depending on both the sequence and chemical environment. The project is therefore to examine the relationship between nucleic acid structure and the preferred sites of damage, by studying the damage process in crystals to identify damage hotspots. This could lead to the ability to predict where damage is most likely to occur in biologically relevant sequences.

In this project you will grow crystals of nucleic acids and develop methods for chemical modification in the crystal state. You will use a variety of state-of-the-art techniques including single-crystal X-ray diffraction (with both variable hydration and in situ screening), synchrotron radiation circular dichroism and UV/visible absorption to study damage in the crystal and solution state, to gain a thorough understanding of how the structure of the nucleic acid directs damage, , working as a part of a team.