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.”
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- Cole, A., Lewis, L., & Walden, H. (2010). The structure of the catalytic subunit FANCL of the Fanconi anemia core complex Nature Structural & Molecular Biology, 17 (3), 294-298 DOI: 10.1038/nsmb.1759
- *Fanconi Anemia pathway (FA) is an important cell signalling pathway – when faults occur it can lead to Fanconi Anaemia, an inherited disorder associated with a range of skeletal abnormalities, short stature, microcephaly, bone marrow failure and a predisposition to a variety of cancers. It is a syndrome that predisposes people to a variety of cancers and other complications. This is because the inability to repair DNA damage leads to long-term accrual of the mistakes in cells that can eventually cause the diseases.
- At least 13 genes are involved in Fanconi Anaemia eight of which form the FA core complex.
- Patients with FA are susceptible to chemotherapy treatments which damage DNA by creating cross links between the two DNA strands which make up a cell’s genetic fingerprint – making it impossible for the cell to replicate its information and divide into daughter cells.