BioWorld International Correspondent

LONDON - New insights into the mechanisms that call a halt to cell division once a cell begins to age could provide clues as to how cancer cells continue multiplying. Researchers in the UK have discovered clusters of molecules around the ends of the chromosomes in cells that have stopped dividing because they have grown old - and many of them have turned out to be known tumor suppressors.

Steve Jackson, deputy director of the Wellcome Trust/Cancer Research UK Institute of Cancer and Developmental Biology in Cambridge, said, "Now that we know how healthy cells age, we can work out how cancer cells ignore this process, which could lead to new treatments for the disease."

As a result of the study, scientists now have a diagnostic marker for aging cells, which could allow them to distinguish between healthy cells and cancer cells.

"This may help us to detect cancer at a very early stage," Jackson said.

Jackson and his colleagues report their study in a paper in Nature (online publication Nov. 5, 2003) titled "A DNA damage checkpoint response in telomere-initiated senescence."

Telomeres are long, repeated sequences at the ends of linear chromosomes. They protect the chromosome ends from fusing together and from degradation by cellular enzymes, rather like the caps on the ends of shoelaces prevent the laces from becoming frayed and tangled.

In normal human cells, telomeres are several thousand bases long. With each round of cell replication, they become progressively shorter until, eventually, they are too short to allow the cell to divide, and it becomes senescent. In cancer cells, however, an enzyme called telomerase is active, allowing the cells to replenish their telomeres and continue to divide.

The researchers set out to investigate whether cells with short telomeres could trigger the same kinds of responses that occur in cells with breaks in double-stranded DNA. Cells with that kind of damaged DNA normally switch on the DNA damage checkpoint response, which stops them from entering the cycle of cell division until the damage to the DNA has been repaired.

The team's experiments showed that the same molecules that repair double-stranded DNA breaks also recognize worn telomeres as genetic damage - and that they have the same effect, sending the cell to sleep and stopping it from dividing.

Jackson and his colleagues found that these molecules formed structures at the ends of telomeres, which they have called senescence-associated DNA damage foci. They found that these structures were present only in senescent cells and not in young cells.

They went on to show that if they blocked the response from the checkpoint molecules, that caused the senescent cells to "wake up" and begin replicating their DNA again. That proves, Jackson said, that the checkpoint machinery was responsible for telling the cell that it was time to stop dividing.

Jackson added: "While we are not yet able to fully reverse the process of cell aging, our study gives us an insight into what happens when a cell grows old. This has important implications for age-related disorders and cancer - a disease in which cells are able to avoid aging."

Philip Reaper, a doctorate student in Jackson's lab and one of the authors of the Nature letter, told BioWorld International: "One of our future priorities is to determine if the senescence-associated DNA damage foci are present in cells from living tissues. If they are, this will considerably extend the significance of our study."

The team also is planning to characterize further the proteins found in the senescence-associated DNA damage foci. In addition, they want to study other types of senescence to find out if similar molecular mechanisms are at work, and whether the molecular complexes that they found around the telomeres also occur consistently around other sites in the genome.

Reaper said: "We think our finding is important because it has been hypothesized for some time that the process of cellular aging is related to activation of the DNA damage response by shortened telomeres. The discovery has implications for our understanding of carcinogenesis because we were able to show that the DNA damage response is required for the cell-cycle arrest phenotype of aged cells, a feature which must be circumvented by developing cancer cells."