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J. Biol. Chem., Vol. 279, Issue 45, 47264-47271, November 5, 2004

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TIN2 Binds TRF1 and TRF2 Simultaneously and Stabilizes the TRF2 Complex on Telomeres^*

Jeffrey Zheng-Sheng Ye¶||, Jill R. Donigian||**, Megan van Overbeek||**, Diego Loayza**, Yan Luo, Andrew N. Krutchinsky¶¶, Brian T. Chait¶¶, and Titia de Lange||||

From the Laboratory for Cell Biology and Genetics, the ^¶¶Laboratory for Mass Spectrometry and Gaseous Ion Chemistry, and the Laboratory for Biochemistry and Molecular Biology, the Rockefeller University, New York, New York 10021 and the Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Human telomeres contain two related telomeric DNA-binding proteins, TRF1 and TRF2. The TRF1 complex contains the TRF1 interacting partner, TIN2, as well as PIP1 and POT1 and regulates telomere-length homeostasis. The TRF2 complex is primarily involved in telomere protection and contains the TRF2 interacting partner human (h)Rap1 as well as several factors involved in the DNA damage response. A prior report showed that conditional deletion of murine TRF1 reduced the presence of TRF2 on telomeres. Here we showed that TRF2 is also lost from human telomeres upon TRF1 depletion with small interfering RNA prompting a search for the connection between the TRF1 and TRF2 complexes. Using mass spectrometry and co-immunoprecipitation, we found that TRF1, TIN2, PIP1, and POT1 are associated with the TRF2-hRap1 complex. Gel filtration identified a TRF2 complex containing TIN2 and POT1 but not TRF1 indicating that TRF1 is not required for this interaction. Co-immunoprecipitation, Far-Western assays, and two-hybrid assays showed that TIN2, but not POT1 or PIP1, interacts directly with TRF2. Furthermore, TIN2 was found to bind TRF1 and TRF2 simultaneously, showing that TIN2 can link these telomeric proteins. This connection appeared to stabilize TRF2 on the telomeres as the treatment of cells with TIN2 small interfering RNA resulted in a decreased presence of TRF2 and hRap1 at chromosome ends. The TIN2-mediated cooperative binding of TRF1 and TRF2 to telomeres has important implications for the mechanism of telomere length regulation and protection.

Received for publication, August 6, 2004 , and in revised form, August 12, 2004.

^* This work was supported by Grants GM49069 and RR00862 from the National Institutes of Health (to T. d. L. and B. T. C., respectively). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by a Mentored Clinical Investigator Award K08CA93604 from the NCI, National Institutes of Health and by The Translational and Integrative Medicine Research Fund from Sloan-Kettering Cancer Institute. Current address: Division of Hematology, Depts. of Medicine and Pharmacology, New York University School of Medicine, 550 First Ave., New York, NY 10016.

^|| These authors contributed equally to this work.

^** Supported by training grants.

Current address: Laboratory of Gene Expression and Regulatory Biology, Institute of Molecular and Cell Biology, 61 Biopolis Dr., Proteos Building, Singapore 138673.

^|||| To whom correspondence should be addressed: Box 159, The Rockefeller University, 1230 York Ave., New York, NY 10021. Tel.: 212-327-8146; Fax: 212-327-7147; E-mail: delange{at}mail.rockefeller.edu.

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