Research carried out by a team including TG Group member Fergus Poynton was published recently in Nature Chemistry. The group of scientists have developed a new technique for looking at the initial steps of DNA oxidation – a process which can lead to DNA damage, mutations and cancers. The breakthrough, which uses DNA in crystals, should help related research in the fields of cancer medicine and drug development.
This work is a collaboration between teams in UCD (led by Dr Susan Quinn) and Trinity College Dublin (led by Professor John Kelly), the University of Reading (led by Professor Christine Cardin, whose BBSRC funded postdoctoral fellow Dr James Hall carried out the crystal growth, sample preparation and sample validation) and the Rutherford Appleton Laboratory (Professor Mike Towrie).
This paper presents the first study of the initial steps of DNA oxidation in crystals. Oxidation of DNA can lead to DNA damage, mutations and cancer and is therefore an extremely active area of research across many scientific disciplines. In this study a ruthenium complex, which has been shown to oxidise DNA when irradiated with light, was crystallised bound to DNA. We have previously demonstrated that when cancer cells are treated with this complex and irradiated with light, the cancer cells undergo cell death, showing the potential of this class of molecule in anti-cancer therapies.
The majority of studies of the interactions of small molecules with DNA are carried out in solution, where there are numerous ways by which these molecules can bind to DNA. This ambiguity complicates interpretation of results and poses a significant challenge to investigators. In this study however, the precise location of the complex bound to DNA is clearly defined in the crystal, therefore removing this uncertainty. This technique has the potential use in the study of other such systems looking at drug-DNA interactions and also looking at photo-damage of DNA associated with UV exposure.
Professor John Kelly from the School of Chemistry at Trinity College Dublin said: “This is an important step in our collaborative work to understand the action of DNA-targeting compounds when they are taken up by cancer cells. Professor Thorri Gunnlaugsson and Professor Clive Williams’ teams at Trinity have previously shown that related compounds can kill such cells when irradiated with visible light.”
The Irish teams have extensive experience in the ultrafast study of DNA, while the Reading group is a world-leader in the X-ray crystallographic analysis of DNA using the Diamond facility. The Rutherford group in the Central Laser Facility has developed extremely sensitive systems for the study of such ultra-fast chemical reactions (as low as a millionth-millionth of a second.).
The work has been supported by SFI/IRC (to Professor Gunnlaugsson) and the BBSRC and a key element of the funding for the collaboration has been provided by the Royal Irish Academy-Royal Society exchange programme.