Blocking tumour repair could improve therapy
a key role in repairing the DNA of cells. The discovery could lead
to a way of inhibiting malignant cells from repairing themselves
after treatment, potentially improving cancer therapy.
When cells divide, breaks occur in their DNA that if not repaired can ultimately cause gene mutations and lead to cancer. An important repair mechanism - called homologous recombination - works to fix these breaks, but up to now scientists had not known the identity of the proteins involved in the final stages of the process.
During recombination, chromosomes become joined and swap segments of genetic information. Now researchers have identified a key protein forming part of the molecular 'scissors' that snip the two chromosomes apart once the damage is repaired.
This insight into the repair process - the culmination of a 15-year search - may provide future drug targets for destroying the ability of cancer cells to repair themselves, enhancing the effectiveness of drug treatments and radiotherapy.
DNA repair is crucial for preserving genome stability and preventing tumours from arising through errors accumulating in DNA. But once cancer has developed, the same repair processes can become an enemy in fighting the disease. Chemotherapy and radiotherapy work by inducing DNA damage but cancer cells are able to harness DNA repair processes to reverse the effects of those treatments.
In the latest study, researchers at Cancer Research UK's London Research Institute studied the process of homologous recombination, which uses one of the two copies of each chromosome in the cell as a template to repair breaks in the damaged copy.
In this process, two complementary chromosomes are held together at a point known as the Holliday junction. Breaks in the DNA are repaired using the information on the undamaged chromosome. The two chromosomes are then snipped apart or cleaved - and it is for this cleaving process that the new protein, called RAD51C, is so important.
Dr Stephen West, who led the research team, said: "While the results won't directly yield treatments for cancer, these new findings give us greater knowledge of how human cells repair damage to their DNA."
"If we can understand how these processes work at the molecular level, then we may be able to devise new ways to inhibit repair and improve cancer therapy," he added.
Dr West's team found that the scissor activity present in extracts made from human cells was lost when they used antibodies to mop up RAD51C. But when they added RAD51C back into the extracts, they found that chromosome separation was restored. They also found that the scissor activity was reduced in mutant cells in which RAD51C was defective.
The new research is published in Science (Vol 303: pp 243-246).
