Sci. Aging Knowl. Environ., 17 August 2005
Alone, protein that replenishes chromosome ends finds capacity to fire up hair stem cells
When actors Ronald Reagan and Jane Wyman split up, she remained a film performer whereas he moved on to politics. Likewise, a protein set free from its partner proves to have an unexpected talent--and this one has stem-cell biologists seeing stars. The protein component of telomerase, famous for maintaining chromosome ends, also stimulates stem cells in hair follicles, new research reveals. The results add to the growing body of evidence that telomerase performs multiple tasks.
Telomerase, which consists of protein and an RNA, keeps chromosome ends from shrinking when cells divide, thus saving the cells from eventually losing the ability to reproduce. Most cells manufacture small amounts of the conglomeration, but output increases in many cancers, allowing indefinite division. Because telomerase can foster cancer even if cells sport long chromosome ends, scientists have postulated that it has skills beyond telomere extension. Several months ago, for example, researchers reported that cells lacking telomerase can't repair their DNA (see "New Trick for an Old Enzyme"). Because mouse stem cells carry luxuriant telomeres, they don't need the duo's lengthening capacity, so Sarin and colleagues wondered whether telomerase might be doing something else.
To find out, the researchers took advantage of hair stem cells from young mice. The cells reside in follicles, and in young mice, they periodically hatch hair-producing cells. These cells eventually slough off, so after a period of rest, the stem cells start making replacements. The team first assessed whether telomerase normally exists in the follicle by measuring telomere-extending activity. Telomerase toiled only when hair grew and not during resting periods.
Then the researchers generated mice that could overproduce on command the protein component, called TERT, in hair stem cells. Triggering TERT manufacture made young animals shaggy due to continuous formation of hair-generating cells. Follow-up biochemical tests confirmed that TERT prompted stem cells in the follicles to divide. Because TERT requires the RNA portion of telomerase to lengthen DNA, the researchers wanted to determine whether the protein component can act by itself to nurture stem cells. Mice in which the gene for the RNA component was obliterated produced similar results, indicating that TERT stands alone on the stem cell podium.
TERT's ability to function without its RNA partner and for novel purposes is surprising researchers. "Off-label telomerase, that's the story," says molecular biologist Elizabeth Blackburn of the University of California, San Francisco. Researchers used to think that the members of the telomerase team acting without each other "would be like one hand clapping," she says, but that view is changing. Unpublished work from her lab and at least one other indicates that TERT can interact with an unidentified protein, suggesting that partnering with other molecules might fuel TERT's "secret life," Blackburn says. Cancer biologist David Fisher of the Dana-Farber Cancer Institute in Boston says that some cancer therapies focus on hindering telomerase's work at chromosome ends, but cancers might have stem cells that fuel malignancy. TERT's newly uncovered ability might promote cancer by stimulating these cells. Drugs that inhibit telomerase "may not be touching this other activity," he says. If scientists want to reel in telomerase, they'll have to view its every role.
August 17, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150