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Scientists iron out system for repairing damaged genes

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by Cancer Research UK | News

14 September 2002

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A brand new mechanism for repairing damaged DNA – using iron molecules as a catalyst – has been discovered by scientists from Cancer Research UK.

Research in this week’s edition of Nature reveals that a molecule called AlkB – fundamental to the repair of genetic damage throughout the natural world – works in a unique manner that could be exploited in future cancer therapies.

Many conventional drugs attack tumours by damaging their DNA and the AlkB molecule seems to play an important role in resistance to these treatments. Interfering with its activity could therefore bring important advances in chemotherapy.

Lead researcher Dr Barbara Sedgwick, of the Cancer Research UK London Research Institute, comments: “The process for repairing DNA has been studied intensively for many years now, so to discover a completely new mechanism of action was both surprising and very exciting.

“We think the AlkB molecule could be one of the major reasons for resistance to chemotherapy and now that we know how it works, it should be possible to find ways to overcome this problem.”

Researchers first discovered AlkB in E. coli bacteria nearly 20 years ago and soon realised the molecule was found in a huge variety of life forms, including humans.

In the new study, scientists extracted AlkB from E coli and recreated the DNA repair process in the test tube. This allowed them to work out exactly which DNA damage the molecule targeted and the precise nature of its mechanism.

They found that AlkB repairs specific chemical changes to two of DNA’s molecular components – adenine and cytosine. Although these changes only account for a small proportion of the total damage occurring to genes, they are believed to be extremely important for a tumour’s response to chemotherapy.

Dr Sedgwick and her colleagues worked out how the repair mechanism functioned by using different combinations of chemicals in the reaction mix, in order to work out which were needed and which were not.

They found that AlkB uses a particular chemical process called oxidative demethylation to repair DNA, relying on the presence of molecules of iron and several other chemicals. The mechanism is quite different from any other repair mechanism yet discovered, although scientists believe other natural processes may work in a similar manner.

Dr Sedgwick adds: “Our discovery is likely to have a number of important implications for the treatment of cancer. Testing for the molecule could help us to predict whether chemotherapy is likely to be successful, while drugs to inhibit it could boost the effectiveness of conventional drugs.

“It might also be possible to use AlkB to protect cells in the bone marrow that can otherwise get damaged by chemotherapy, which may reduce the side-effects of treatment.”

Sir Paul Nurse, Chief Executive of Cancer Research UK, says: “Our cells are constantly suffering genetic damage and without systems for patching up our DNA they’d quickly die as a result.

“Chemotherapy tries to take advantage of the lethal effects of DNA damage to kill cancer cells, but sometimes our natural repair systems get in the way and cause resistance to treatment. One of those systems involves AlkB, so knowing how the molecule works is an important development.”