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Molecular and Cellular Biology, September 2008, p. 5251-5264, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00048-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Distinct Functions of POT1 at Telomeres {triangledown} ,{dagger}

Katharine S. Barrientos,{ddagger} Megan F. Kendellen,{ddagger} Brian D. Freibaum, Blaine N. Armbruster,§ Katherine T. Etheridge, and Christopher M. Counter*

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

Received 10 January 2008/ Returned for modification 13 March 2008/ Accepted 20 May 2008

The mammalian protein POT1 binds to telomeric single-stranded DNA (ssDNA), protecting chromosome ends from being detected as sites of DNA damage. POT1 is composed of an N-terminal ssDNA-binding domain and a C-terminal protein interaction domain. With regard to the latter, POT1 heterodimerizes with the protein TPP1 to foster binding to telomeric ssDNA in vitro and binds the telomeric double-stranded-DNA-binding protein TRF2. We sought to determine which of these functions—ssDNA, TPP1, or TRF2 binding—was required to protect chromosome ends from being detected as DNA damage. Using separation-of-function POT1 mutants deficient in one of these three activities, we found that binding to TRF2 is dispensable for protecting telomeres but fosters robust loading of POT1 onto telomeric chromatin. Furthermore, we found that the telomeric ssDNA-binding activity and binding to TPP1 are required in cis for POT1 to protect telomeres. Mechanistically, binding of POT1 to telomeric ssDNA and association with TPP1 inhibit the localization of RPA, which can function as a DNA damage sensor, to telomeres.

* 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

{triangledown} Published ahead of print on 2 June 2008.

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

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

§ Present address: Millipore Corporation, St. Charles, MO.

Molecular and Cellular Biology, September 2008, p. 5251-5264, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00048-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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