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Molecular and Cellular Biology, March 2004, p. 1944-1955, Vol. 24, No. 5
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.5.1944-1955.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Functional Subdomain in the Ankyrin Domain of Tankyrase 1 Required for Poly(ADP-Ribosyl)ation of TRF1 and Telomere Elongation

Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 170-8455,¹ Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan,³ The Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016²

Received 26 September 2003/ Returned for modification 10 November 2003/ Accepted 21 November 2003

In human cells, telomere elongation by telomerase is repressed in cis by the telomeric protein TRF1. Tankyrase 1 binds TRF1 via its ankyrin domain and poly(ADP-ribosyl)ates it. Overexpression of tankyrase 1 in telomerase-positive cells releases TRF1 from telomeres, resulting in telomere elongation. The tankyrase 1 ankyrin domain is classified into five conserved subdomains, ARCs (ankyrin repeat clusters) I to V. Here, we investigated the biological significance of the ARCs. First, each ARC worked as an independent binding site for TRF1. Second, ARCs II to V recognized the N-terminal acidic domain of TRF1 whereas ARC I bound a discrete site between the homodimerization and the Myb-like domains of TRF1. Inactivation of TRF1 binding in the C-terminal ARC, ARC V, either by deletion or point mutation, significantly reduced the ability of tankyrase 1 to poly(ADP-ribosyl)ate TRF1, release TRF1 from telomeres, and elongate telomeres. In contrast, other ARCs, ARC II and/or IV, inactivated by point mutations still retained the biological function of tankyrase 1. On the other hand, ARC V per se was not sufficient for telomere elongation, suggesting a structural role for multiple ARCs. This work provides evidence that specific ARC-TRF1 interactions play roles in the essential catalytic function of tankyrase 1.

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