Viewing DNA Damage with Crystal Clarity

Posted on: 21 October 2015

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.

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 Science and Technology Facilities Council (STFC, 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. STFC's 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.