Sci. Aging Knowl. Environ., 1 June 2005
New Trick for an Old Enzyme
Famous as a chromosome capper, telomerase might also orchestrate general DNA repair
Telomerase doesn't just work for tips. The enzyme rebuilds telomeres, the protective caps on chromosomes, but new work suggests it also helps cells repair damaged DNA elsewhere. The results might help doctors tailor treatments to kill cancer cells.
Telomeres shrink with every cell division unless telomerase spruces them up. If telomeres wear down, many cells in culture settle into a semidormant state known as senescence, in which they can't divide (see "More Than a Sum of Our Cells"). Most body cells shut down telomerase most of the time. Cancer cells, by contrast, often pump out the enzyme, allowing them to duplicate indefinitely. Some studies hint that telomerase performs other jobs besides tending telomeres. For example, 2 years ago cancer biologist William Hahn of Harvard Medical School in Boston and colleagues showed that some human cells turn on telomerase just before they divide. But this burst of activity doesn't spare their telomeres, suggesting that telomerase fills another role. The researchers also found that certain connective tissue cells lacking telomerase can slip into senescence even with long telomeres. DNA damage can drive cells into senescence, Hahn notes, so his group decided to test for a link between telomerase and DNA breakage.
The researchers first quashed telomerase activity in human connective tissue cells. They then dosed the cultures with DNA-breaking radiation or chemicals. DNA injury usually triggers cells to affix phosphate molecules to several proteins, including H2AX, which then help coordinate repair. However, the telomerase-deprived cells didn't show this surge in phosphate addition. Cells also respond to DNA fractures by hiking the quantity of p53, a protein that halts division so that molecular fix-it crews can restore the strands. In the telomerase-deficient cells, however, p53 production didn't climb after DNA damage. The team also found that these cells died rapidly when exposed to radiation, an indication that they can't restore their DNA. Next, the researchers engineered cells to produce a telomerase that can't bestow cellular immortality but can refurbish telomeres in the test tube. Cells that made the addled enzyme lost their chromosome caps, but they could still fire up p53 and add phosphates to H2AX, suggesting that telomerase's DNA-renovating capacity is separate from its work at telomeres. Further experiments indicate that removing telomerase alters how DNA coils up in the cell. Overall, the study indicates that telomerase helps govern the activity of the cell's DNA-repair machinery, possibly by modifying chromosome architecture, Hahn says.
The findings support the idea that telomerase has another job besides lengthening telomeres, says molecular biologist Lea Harrington of the University of Toronto in Canada. But further research must verify that telomerase isn't making subtle changes to telomeres that prompt DNA repair, she adds. The work also explains why telomerase output surges in some cells before division, says molecular biologist Steven Artandi of Stanford University in California: "That small amount [of telomerase] is important" for mending DNA. Blocking the repair activity of telomerase might make cancer cells more vulnerable to radiation and chemotherapy, Hahn adds. Coaxing the enzyme to take a vacation might pay off for cancer patients.
June 1, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150