title: Telomere protection by TPP1/POT1 requires tethering to TIN2.
abstract: To prevent ATR activation, telomeres deploy the single-stranded DNA binding activity of TPP1/POT1a. POT1a blocks the binding of RPA to telomeres, suggesting that ATR is repressed through RPA exclusion. However, comparison of the DNA binding affinities and abundance of TPP1/POT1a and RPA indicates that TPP1/POT1a by itself is unlikely to exclude RPA. We therefore analyzed the central shelterin protein TIN2, which links TPP1/POT1a (and POT1b) to TRF1 and TRF2 on the double-stranded telomeric DNA. Upon TIN2 deletion, telomeres lost TPP1/POT1a, accumulated RPA, elicited an ATR signal, and showed all other phenotypes of POT1a/b deletion. TIN2 also affected the TRF2-dependent repression of ATM kinase signaling but not to TRF2-mediated inhibition of telomere fusions. Thus, while TIN2 has a minor contribution to the repression of ATM by TRF2, its major role is to stabilize TPP1/POT1a on the ss telomeric DNA, thereby allowing effective exclusion of RPA and repression of ATR signaling.
authors.affiliation: Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Kaori K
authors.initials: KK
authors.lastname: Takai
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kibe
authors.forename: Jill R
authors.initials: JR
authors.lastname: Donigian
authors.forename: David
authors.initials: D
authors.lastname: Frescas
authors.forename: Titia
authors.initials: T
authors.lastname: de Lange
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004277:DNA, Single-Stranded / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000089804:Shelterin Complex; D015398:Signal Transduction / Q000235:genetics*; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics / Q000378:metabolism
chemical_list: C495876:ACD protein, human; C544060:Acd protein, mouse; D018797:Cell Cycle Proteins; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; C507326:POT1 protein, mouse; D011994:Recombinant Proteins; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; C499083:Tinf2 protein, mouse; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
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