Structure Of A key Part Of Telomerase

In work that could help lead to anticancer therapeutics, researchers have obtained the first 3-D atomic structure of an essential part of the telomerase enzyme. Previously, telomerase could not be structurally analyzed due to technical problems in obtaining suitable crystals. The new study reports the first-ever structure of any piece of the enzyme.

Telomerase catalyzes the extension and maintenance of telomeres (chromosome end caps), which wear away with successive cell divisions. Telomerase is expressed selectively in cancer cells, "immortalizing" the cells (making them capable of dividing in perpetuity). Agents that inhibit telomerase are being investigated as potentially selective anticancer agents. But such studies have been hampered by a lack of structural information on the enzyme.

Howard Hughes Medical Institute President Thomas R. Cech and coworkers Steven A. Jacobs and Elaine R. Podell have now taken a step toward addressing this problem. They determined the high-resolution crystal structure of an important part of telomerase from the ciliated protozoan Tetrahymena thermophila: the catalytically essential N-terminal domain of the enzyme's reverse transcriptase unit (Nat. Struct. Mol. Biol., published online Feb. 5, dx.doi.org/10.1038/nsmb1054). The structure reveals a key groove that telomerase uses to grab DNA. The groove is therefore a promising target for potential inhibitors.

"The work appears solid and is a major advance in the field," says Jerry W. Shay, an expert on telomeres, telomerase, and cancer at the University of Texas Southwestern Medical Center, Dallas. "It has been and continues to be a challenge to produce significant amounts of full-length telomerase protein, which is needed to make crystals. This work used a small portion of the amino terminus of telomerase reverse transcriptase and was successful."