POT1 association with TRF2 regulates telomere length.
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(DeltaOB) mutant protein. POT1 is known to associate with two proteins through the protein interaction domain retained in POT1(DeltaOB)-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(DeltaOB) to promote telomere elongation. Mechanistically, expression of POT1(DeltaOB) 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(DeltaOB). 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.
Kendellen
Megan F
MF
Department of Pharmacology and Cancer Biology, Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Barrientos
Katharine S
KS
Counter
Christopher M
CM
D015815:Cell Adhesion Molecules / Q000378:metabolism*; D006801:Humans; D000089804:Shelterin Complex; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
C495876:ACD protein, human; D015815:Cell Adhesion Molecules; C440849:POT1 protein, human; D000089804:Shelterin Complex; C504753:TERF2 protein, human; C085434:TINAG protein, human; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; D020827:rap1 GTP-Binding Proteins