Overactive telomerase has potentially lethal consequences far beyond the propagation of erroneous DNA. The enzyme is particularly lively within cancer cells, which prevents them from dying out naturally. Finding a way to turn off telomerase in cancer cells might help prevent the diseased cells from multiplying.
Flipping the switch on telomerase might mean stopping it from forming in the first place, said Feigon.
"Any time you want to stop an enzyme, you can target activity, but you can also target assembly," she said. "If you keep it from assembling, that's just as good as keeping it from being active, because it never even forms."
While there is enormous interest in telomerase due to its connection to cancer and aging, very little is known about its three-dimensional structure or its formation, Feigon said.
Four years ago, UCLA postdoctoral scholar Mahavir Singh set out to determine how a strand of RNA and multiple proteins bind together to form telomerase. He set his sights on the p65 protein, one of the key components of the enzyme. Like many proteins, p65 is a long chain of both stiff and supple links that fold in upon one another in a prescribed pattern. At the very end of the p65 protein is a floppy, disordered tail.
"We knew the tail was important for the protein's function, but it wasn't clear how or why," said Singh, first author of the current study. "From the structure, it became evident how it interacts with the telomerase RNA."
When Singh snipped off the flexible tail from p65, he found that the assembly of telomerase became severely limited. The tailless p65 simply couldn't help put together the enzyme.
Using both X-ray crystallography and nuclear magnetic resonance spectroscopy, Singh probed the structure of the protein and its interaction with telomerase RNA. He found that upon assembly, the flexible tail transforms into a rigid crowbar that pries apa
|Contact: Stuart Wolpert|
University of California - Los Angeles