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Telomerase 3-D structure identified
Telomerase, a key enzyme in cells, and subsequent telomeres, have been discovered by researchers in Berkeley several years ago, leading to the 2006 Nobel Prize in medicine and physiology. Ever since its discovery, researchers have toiled to identify its complete structure and discover it’s 3-D configuration with little success. Finally, in the April 11th edition of Nature magazine, a paper has been published as the result of collaboration between researchers from UCLA and UC Berkeley, containing the complete structure of telomerase, including a 3-D model of the elusive enzyme.
"We combined every single possible method we could get our hands on to solve this structure and used cutting-edge technological advances," said co-author Jiansen Jiang, a researcher who works the study's co-senior author, Z. Hong Zhou, director of the Electron Imaging Center for Nanomachines at the California NanoSystems Institute at UCLA and a professor of microbiology, immunology and molecular genetics. "This breakthrough would not have been possible five years ago."
The culmination of decade’s worth of biochemical analysis combined with new imaging and scanning technologies has yielded in satisfying results.
"We really had to figure out how everything fit together, like a puzzle," said co-first author Edward Miracco, a National Institutes of Health postdoctoral fellow in Feigon's laboratory. "When we started fitting in the high-resolution structures to the blob that emerged from electron microscopy, we realized that everything was fitting in and made sense with decades of past biochemistry research. The project just blossomed, and the blob became a masterpiece."

Telomerase is an enzyme present in all living cells containing genes. Its function is to maintain telomeres, structures at the ends of DNA strands that serve to protect the valuable genetic material from being damaged. Telomeres act like caps at the ends of shoelaces; they keep the strands of DNA from “untangling” and being damaged by external factors. While, in all healthy cells, telomeres progressively get shorter with every division, and finally, incite cellular death when telomeres become too short to effectively protect DNA; a normal part of ageing, cancer cells work differently. More than 90% of cancer cells contain much greater amounts of telomerase, leading to their apparent “immortality” and ability to propagate almost endlessly. This new study provides tremendous value in biopharmaceutical research, allowing researchers to not only study the complex interactions of telomerase in tumorigenic cells, but also to start designing drugs that can target telomerase directly, thus shortening the life-span of tumorigenic cells significantly. Until now, designing drugs that target telomerase specifically has been like shooting in the dark, but now it is quite possible and plausible.

"Inhibiting telomerase won't hurt most healthy cells but is predicted to slow down the progression of a broad range of cancers. Our structure can be used to guide targeted drug development to inhibit telomerase, and the model system we used may also be useful to screen candidate drugs for cancer therapy."
The researchers successfully solved the structure of telomerase in Tetrahymena thermophila, a single-celled eukaryote in which telomerase and telomeres were first identified. Research on Tetrahymena telomerase in the lab of co-senior author Kathleen Collins, a professor of molecular and cell biology at UC Berkeley, laid the groundwork for the structure to be solved. "The success of this project was absolutely dependent on the collaboration among our research groups. At every step of this project, there were difficulties," Feigon said. "We had so many technical hurdles to overcome, both in the electron microscopy and biochemistry. Pretty much every problem we could have, we had, and yet at each stage these hurdles were overcome in an innovative way."
One of the biggest surprises for the researchers has been the apparent involvement of P50, a protein which acts as a hinge in telomerase, to allow movement within the complex. P50 has been shown to also play a key-role in enzymatic functions of telomerase as well as recruiting proteins to join the complex.

The beauty of this structure is that it opens up a whole new world of questions for us to answer. The exact mechanism of how this complex interacts with the telomere is an active area of future research." –Feigon finally said.

Study published in April 11th Edition of Nature
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