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Molecular and Cellular Biology, October 2009, p. 5611-5619, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.00286-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

POT1 Association with TRF2 Regulates Telomere Length{triangledown},{ddagger}

Megan F. Kendellen,{dagger} Katharine S. Barrientos,{dagger} and Christopher M. Counter*

Department of Pharmacology and Cancer Biology, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina

Received 4 March 2009/ Returned for modification 26 March 2009/ Accepted 24 July 2009

Deleting the OB folds encoding the telomeric single-stranded DNA (ssDNA)-binding activity of the human telomeric protein POT1 induces significant telomere elongation, suggesting that at least one critical aspect of the regulation of telomere length is disrupted by this POT1{Delta}OB mutant protein. POT1 is known to associate with two proteins through the protein interaction domain retained in POT1{Delta}OB—the telomeric double-stranded DNA-binding protein TRF2 and the telomere-associated protein TPP1. We report that introducing a mutation that reduces association of POT1 with TRF2, but not a mutation that reduces the association with TPP1, abrogates the ability of POT1{Delta}OB to promote telomere elongation. Mechanistically, expression of POT1{Delta}OB reduced the association of TRF2 with POT1, RAP1, and TIN2; however, of these proteins, only ectopic expression of POT1 suppressed the telomere elongation induced by POT1{Delta}OB. Lastly, replacing endogenous POT1 with a full-length POT1 mutant defective in the association with TRF2 induced telomere elongation. Thus, we conclude that the association of POT1 with both ssDNA and TRF2 is critical for telomere length homeostasis.

* Corresponding author. Mailing address: Department of Pharmacology and Cancer Biology, Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-9890. Fax: (919) 684-8958. E-mail: count004{at}mc.duke.edu

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{triangledown} Published ahead of print on 3 August 2009.

{dagger} M. F. Kendellen and K. S. Barrientos contributed equally to this work.

Molecular and Cellular Biology, October 2009, p. 5611-5619, Vol. 29, No. 20
0270-7306/09/$08.00+0     doi:10.1128/MCB.00286-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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