The majority of studies on DNA interactions with small molecules, such as drugs, have previously been carried out in solution. Such a medium presents difficulties because there are lots of different ways for the drugs to bind to the DNA.
However, the crystallography technique explained in the current study just published in leading international journal Nature Chemistry paves the way for the fine-grained study of other systems where the location of the drug is defined.
Dr Susan Quinn from the School of Chemistry at University College Dublin is the lead author of the study. She said: “These results are very exciting as they demonstrate the ability to follow the flow of electrons from an individual DNA base to a bound molecule whose exact position in known and this is an enormous advantage in the study of the early events that lead to oxidative DNA damage.”
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 current study also opens the door for studies looking at direct UV excitation of DNA in crystals, which should help us gain an understanding of the processes that cause DNA photo-damage (and hence lead to DNA mutations). These chemical reactions take place very rapidly (typically in less than a billionth of a second).
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).
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.
The history behind the breakthrough
Professor Kelly began researching lasers, ruthenium complexes and DNA back in the early 1980s. He began collaborating with the Rutherford laser lab in 2001, to observe the ultrafast electron transfer reactions between ruthenium complexes and DNA (in solution), which leads to guanine oxidation.
From 2005 onwards, he began working with Dr Quinn, and in 2010, a group comprising his then SFI-funded postgraduate student Kyra O’Sullivan and James Hall, a student of Professor Chris Cardin (a former Trinity Fellow), managed to obtain the first crystals of ruthenium complexes intercalated into small DNA molecules. This was a major achievement in its own right and paved the way for the big breakthrough to be made.
In March 2013 in the Rutherford Laser Laboratory, a Trinity-Reading team led by Professor Kelly (and with key roles played by Fergus Poynton (a postgraduate student of Trinity Biomedical Siences Institute-based Professor Gunnlaugsson), Paraic Keane, and James Hall, then a student of Professor Cardin) obtained the first infra-red measurements from these DNA crystals.
This result allowed the team to put forward a three-year research programme for access to the Rutherford laboratory. The first results of a very thorough study of the system carried out by Dr Susan Quinn (UCD) and James Hall have just been published in Nature Chemistry.
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