Structure of 'DNA repair engine' that reverses beneficial effects of chemotherapy deciphered

Feb 15 2010

Ignition switch key to chemotherapy reversal

Cancer Research UK scientists have deciphered the first structure of 'a DNA repair engine' that reverses the beneficial effects of chemotherapy, according to research published in Nature Structural and Molecular Biology today.

The team at Cancer Research UK's London Research Institute have reconstructed in crystal form the protein called FANCL which is at the heart of a vital DNA repair pathway called Fanconi Anaemia pathway (FA).

The FA pathway can repair the tumour-destroying damage to cancer cells delivered by chemotherapy. As such it is a potential target for new drugs to 'switch off' the repair of such damage - and increase the effectiveness of chemotherapy.

Dr Helen Walden, lead investigator at Cancer Research UK's London Research Institute said: "Our team has determined the structure of the engine in the cell's maintenance pack that if switched off would make cells much more responsive to chemotherapy. We have taken the first full atomic snapshot of a protein in this cell repair pathway, right at the very heart of the route by which cancer cells defend themselves against treatments which are intended to destroy them.

"By blocking this repair 'ignition switch' it may be possible to boost traditional treatments. As such, it's a drug target."

The FA core complex is key to the cell's repair pathway. Until now a lack of structural information on this pathway has hindered a complete molecular understanding of associated diseases including cancer and made it more difficult to develop effective treatments to block it.

Dr Lesley Walker, Cancer Research UK's director of cancer information, said: "This is important research which gets right to the heart of a tactic that cancer cells use to shield themselves from chemotherapy.

"These findings give us a promising target for potential drugs to 'soften up' cancer cells as chemotherapy is delivered - to make it as effective as possible."