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Molecular and Cellular Biology, February 2002, p. 1253-1265, Vol. 22, No. 4
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.4.1253-1265.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Functional Multimerization of Human Telomerase Requires an RNA Interaction Domain in the N Terminus of the Catalytic Subunit

Tara J. Moriarty, Sylvain Huard, Sophie Dupuis, and Chantal Autexier*

Anatomy and Cell Biology Department, McGill University, Montréal, Québec, Canada H3A 2B2, and Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montréal, Québec, Canada H3T 1E2

Received 17 October 2001/ Returned for modification 15 November 2001/ Accepted 26 November 2001

Functional human telomerase complexes are minimally composed of the human telomerase RNA (hTR) and a catalytic subunit (human telomerase reverse transcriptase [hTERT]) containing reverse transcriptase (RT)-like motifs. The N terminus of TERT proteins is unique to the telomerase family and has been implicated in catalysis, telomerase RNA binding, and telomerase multimerization, and conserved motifs have been identified by alignment of TERT sequences from multiple organisms. We studied hTERT proteins containing N-terminal deletions or substitutions to identify and characterize hTERT domains mediating telomerase catalytic activity, hTR binding, and hTERT multimerization. Using multiple sequence alignment, we identified two vertebrate-conserved TERT N-terminal regions containing vertebrate-specific residues that were required for human telomerase activity. We identified two RNA interaction domains, RID1 and RID2, the latter containing a vertebrate-specific RNA binding motif. Mutations in RID2 reduced the association of hTR with hTERT by 50 to 70%. Inactive mutants defective in RID2-mediated hTR binding failed to complement an inactive hTERT mutant containing an RT motif substitution to reconstitute activity. Our results suggest that functional hTERT complementation requires intact RID2 and RT domains on the same hTERT molecule and is dependent on hTR and the N terminus.

* Corresponding author. Mailing address: Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, The Sir Mortimer B. Davis Jewish General Hospital, 3755 Côte Ste. Catherine Rd., Montréal, Québec, Canada H3T 1E2. Phone: (514) 340-8222, ext. 4651. Fax: (514) 340-8295. E-mail: chantal.autexier{at}mcgill.ca.

Molecular and Cellular Biology, February 2002, p. 1253-1265, Vol. 22, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.4.1253-1265.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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