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Structure of the Tribolium castaneum telomerase catalytic subunit TERT

Abstract

A common hallmark of human cancers is the overexpression of telomerase, a ribonucleoprotein complex that is responsible for maintaining the length and integrity of chromosome ends. Telomere length deregulation and telomerase activation is an early, and perhaps necessary, step in cancer cell evolution. Here we present the high-resolution structure of the Tribolium castaneum catalytic subunit of telomerase, TERT. The protein consists of three highly conserved domains, organized into a ring-like structure that shares common features with retroviral reverse transcriptases, viral RNA polymerases and B-family DNA polymerases. Domain organization places motifs implicated in substrate binding and catalysis in the interior of the ring, which can accommodate seven to eight bases of double-stranded nucleic acid. Modelling of an RNA–DNA heteroduplex in the interior of this ring demonstrates a perfect fit between the protein and the nucleic acid substrate, and positions the 3′-end of the DNA primer at the active site of the enzyme, providing evidence for the formation of an active telomerase elongation complex.

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Figure 1: The structure of TERT.
Figure 2: The TERT domain fold and main signature motifs.
Figure 3: Model of the TERT–RNA–DNA complex.
Figure 4: The active site and nucleotide-binding pocket of telomerase.
Figure 5: Localization of the RNA–DNA ends in the interior of the ring.

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Accession codes

Primary accessions

Protein Data Bank

Data deposits

The atomic coordinates and structure factors have been deposited in the Protein Data Bank under accession numbers 3DU5 and 3DU6.

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Acknowledgements

We thank R. Marmorstein for critical reading of this manuscript. This project was funded by the Pennsylvania Department of Health and The Ellison Medical Foundation.

Author Contributions E.S. designed the experimental plan, carried out the research and wrote the paper. A.J.G. and A.P.S. assisted with the experimental work.

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Correspondence to Emmanuel Skordalakes.

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Gillis, A., Schuller, A. & Skordalakes, E. Structure of the Tribolium castaneum telomerase catalytic subunit TERT. Nature 455, 633–637 (2008). https://doi.org/10.1038/nature07283

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