Photo by Todd McNaught
Cells have evolved extraordinarily elegant strategies to repair broken chromosomes. But like a driver whose tailpipe falls off a long way from home, they aren't above resorting to a little duct tape in an emergency.
A recent study by researchers in the Basic Sciences Division has found that a protein in baker's yeast called Ku may be the molecular equivalent of the versatile sticky stuff, providing cells with a slipshod but better-than-nothing fix for mending a damaged genetic blueprint.
The findings have implications that are likely to go far beyond the health of yeast cells. The scientists speculate that an analogous process in human cells may endow cancer cells with the means to cope with their characteristically massive amounts of chromosome damage, since human cells-and virtually all cells that have been studied-contain a version of the Ku protein.
The study reveals a previously unsuspected function for Ku, which is best known for its role in keeping the natural ends of chromosomes, called telomeres, intact and for its role in a more efficient type of DNA repair, said Dr. Anne Stellwagen, a postdoc in Dr. Dan Gottschling's lab who led the study. Co-authors of the paper, published in the Oct. 1 issue of Genes and Development, were research technician Zara Haimberger and graduate student Joshua Veatch.
"Ku is a multifunctional protein, found both at telomeres-the true ends of chromosomes-and at chromosome breaks," Stellwagen said. "It's been known for some time, in many types of cells, that Ku is important for a type of DNA repair that joins the two broken ends together, a process that helps to minimize the loss of any genetic information."
This end-joining method is one of two highly efficient DNA repair systems found in most cell types. Occasionally, though, cells instead opt for the molecular equivalent of a duct-tape patch and simply tack a telomere onto a broken end, which results in the loss of all DNA from the other side of the break. Ku, Stellwagen has found, turns out to play a role in this healing mechanism as well-but why it would opt for this method over its more efficient counterpart is open to speculation.
"In order to do DNA end-joining, which is a much safer form of DNA repair, Ku needs to hold onto both broken chromosome ends," Stellwagen said. "But if Ku were to lose its grip on one end, then adding a telomere is better than nothing, because it gives the cell a chance to survive.
Stellwagen's discovery of Ku's role in the last-ditch repair process grew from previous work in Gottschling's lab on Ku's function at telomeres. Using a mutant version of Ku that she constructed, Stellwagen showed that Ku binds to an enzyme that rebuilds chromosome ends, called telomerase. This property presumably enables Ku to deliver telomerase to native chromosome ends as well as to damage-induced breaks. Because many studies have found that tumors contain active telomerase while healthy human tissue does not, the Ku-telomerase association also could help to explain how cancer cells manage to propagate despite the extensive DNA damage that is their hallmark.
"Telomerase gets turned off in most healthy human cells, but it's turned back on in virtually every type of tumor that has been studied," Stellwagen said. "It's been thought that this is primarily to allow tumor cells to regenerate telomeres-which get progressively shorter occurs during each round of cell division-because cancer cells divide indefinitely, while normal cells do not.
"But our work suggests that in addition to endowing cancer cells with a longer lifespan, active telomerase may provide tumor cells with a mechanism to heal DNA damage by being recruited to chromosome breaks by Ku."
In support of this idea, other laboratories have found that healthy human cells that have been manipulated to contain active telomerase can tolerate DNA damage from radiation better than healthy cells that lack telomerase, even though both cell types are equally good at repairing DNA through the more effective healing pathways.
Ku's affinity for broken chromosome ends in cancer cells has more staying power than the duct tape holding up a broken tailpipe. Still, Stellwagen said that it's possible that Ku's association with telomerase could be dissolved with a little scientific ingenuity.
"In our study, we were able to identify the part of Ku that binds to telomerase," she said. "It might be possible to create drugs that specifically target this region of Ku and thereby thwart a mechanism that allows cancer cells to grow."