BioWorld Internatio

LONDON - Identification of a new mechanism that allows cells to remain immortal could lead to novel therapies for about 10 percent of cancer cases, recent research suggests.

The discovery centers on the function of an enzyme called RAD51D. It already was known to play a role in repairing DNA, but the latest research suggests that it also helps to regulate the lengths of the telomeres that cap the ends of the chromosomes.

Madalena Tarsounas, of the Cancer Research UK London Research Institute in South Mimms, said, "Understanding how cancer cells remain eternally young has been a key focus of research for more than a decade, so it's particularly exciting to have made such a striking discovery."

Commenting on the work, which was jointly funded by the charities Cancer Research UK and the Breast Cancer Campaign, Pamela Goldberg, chief executive of the Breast Cancer Campaign, said: "By avoiding cell death, cancer cells are able to have unique control in the human body. This research has discovered an important element, which appears to be essential in sidestepping cell death. If we can in some way control this, we may be able to stop the growth and spread of cancer cells."

A report of the work appears in the April 30, 2004, issue of Cell in a paper titled "Telomere Maintenance Requires the RAD51D Recombination/Repair Protein." Tarsounas and her colleagues write, "To our knowledge, this study provides the first direct visualization of the stable association of a homologous recombination/repair protein with mammalian telomeres."

Telomeres are the repetitive strips of DNA found at the ends of chromosomes. Each time a cell divides, the telomeres get shorter until eventually they disappear altogether, and the cell enters the pathway leading to apoptosis (programmed cell death).

Cancer cells circumvent the shortening of the telomeres, either by using the enzyme telomerase to add DNA onto the ends of the chromosomes, or in other ways - for example, using the enzymes that normally are involved in repairing damage to DNA caused by chemicals or radiation.

Tarsounas and her colleagues suggest that, in normal cells, RAD51D might stabilize the telomeres without interfering with the "timer" that limits their life span. In cancer cells, however, RAD51D may be overactive, allowing the cells to grow and divide indefinitely.

A spokesman for Cancer Research UK said, "Drugs to block the action of RAD51D could potentially be effective against many different tumors, by stripping cancer cells of their immortality."

According to Tarsounas, up to 10 percent of tumors may rely on the new mechanism to keep their cells alive. "These tumors may also be highly susceptible to drugs targeted against RAD51D," she said. "As well as opening the way to new types of treatment for cancer, our study has shed light on the complex but intriguing processes, which control how and when we get old."

The team had focused on the group of enzymes known as RAD51, as earlier studies had shown they were required if cells were to respond normally to DNA-damaging agents. RAD51D seemed to be particularly important: Knockout mice lacking that gene died as embryos.

Tarsounas and her colleagues decided to investigate precisely where RAD51D could be found in cells. They used monoclonal antibodies to RAD51D, labeled with an immunofluorescent chemical. They found that RAD51D localized to the telomeres of the chromosomes in both somatic cells and those undergoing meiosis.

The team also tried to block the activity of RAD51D. When they added small interfering RNA molecules targeted at RAD51D to cells, most of the cells died within seven days. They were able to show that the loss of cell viability was associated with levels of RAD51D that were 50 percent lower than normal, and that the type of cell death that occurred was due to apoptosis.

Further experiments demonstrated that in cells to which they had added siRNA targeted at RAD51D, the telomeres on the chromosomes were more likely to be shorter, and less likely to be longer, than normal. Knocking out the function of RAD51D resulted in a statistically significant reduction in telomere length, the researchers found.