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Originally published In Press as doi:10.1074/jbc.M111068200 on December 18, 2001

J. Biol. Chem., Vol. 277, Issue 10, 8538-8544, March 8, 2002
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Two Independent Regions of Human Telomerase Reverse Transcriptase Are Important for Its Oligomerization and Telomerase Activity*

Kuniaki AraiDagger §, Kenkichi Masutomi§, Shilagardy KhurtsDagger , Shuichi Kaneko§, Kenichi Kobayashi§, and Seishi MurakamiDagger

From the Dagger  Department of Molecular Oncology, Cancer Research Institute, and the § First Department of Internal Medicine, Kanazawa University, Takarama-machi 13-1, Kanazawa 920-0934, Japan

Human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, contains motifs conserved among reverse transcriptases. Several nucleic acid-dependent polymerases that share a "fingers, palm, and thumb substructure" were shown to oligomerize. Here we demonstrate that hTERT also has this ability using partially purified recombinant hTERTs and mammalian cells co-expressing differently tagged hTERTs. Human template RNA (hTR), by contrast, has no effect on the structural oligomerization of hTERTs. Therefore, hTERT has an intrinsic ability of oligomerization in the absence of hTR. We identified two separate regions as essential for the oligomerization. The regions, amino acids 301-538 (amino-terminal region) and amino acids 914-928 (carboxyl-terminal region), are outside the fingers and palm substructure covering motif T to D and interact with each other in vivo. A substituted mutant of hTERT, hTERT-D712A-V713I, which was reported as a dominant negative form of hTERT, bound to the wild-type hTERT and inhibited its telomerase activity transiently expressed in telomerase-negative finite normal human fibroblast. The truncated forms of hTERT containing the binding region to the wild-type hTERT partially inhibited the telomerase activity, probably by preventing the wild-type hTERT from forming an oligomer. Taken together, the oligomerization of hTERT is an important step for telomerase activity.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 81-76-265-2731; Fax: 81-76-234-4501; E-mail: semuraka@kenroku.kanazawa-u.ac.jp.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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