Scientists grasp DNA repair 'scissors'

Cancer Research UK

Cancer Research UK scientists have discovered a key protein that cells use to repair their DNA and protect us from cancer, a report in Science1 reveals.

When cells divide, breaks occur in their DNA that if not repaired can ultimately 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 'scissors' that snip the two chromosomes apart once the damage is repaired. This fundamental insight into the repair process - the culmination of a 15-year search - may provide future 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.

Researchers at Cancer Research UK's London Research Institute studied an important repair process called homologous recombination. This repairs DNA breaks by using one of the two copies of each chromosome in the cell as a template to repair breaks in the damaged copy.

With homologous recombination, 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 protein, called RAD51C, is so important.

The team has found that RAD51C is a key component of the molecular scissor that clips the two chromosomes apart and completes the recombination process.

Dr Stephen West says: "This is a major step forward in understanding an important stage in DNA repair. The findings are the culmination of a long search, as it is not easy to isolate individual proteins from the myriad that exist in cells.

"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."

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.

Professor Robert Souhami, Cancer Research UK's Director of Clinical and External Affairs, says: "Many cancer treatments work by causing lethal DNA damage in cancer cells. But if cancer cells are able to repair damaged DNA they can often survive the effects of treatment. Once we understand the many ways in which DNA repair is brought about, we can look for new ways to inhibit the process in cancer cells, making them more susceptible to treatment.

"The team has searched long and hard to find this important DNA repair protein - and have added a great deal to our fundamental understanding of cells and how they maintain the integrity of DNA."

ENDS

  1. Science303 pp.243-246