title: TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling.
abstract: The semiconservative replication of telomeres is facilitated by the shelterin component TRF1. Without TRF1, replication forks stall in the telomeric repeats, leading to ATR kinase signaling upon S-phase progression, fragile metaphase telomeres that resemble the common fragile sites (CFSs), and the association of sister telomeres. In contrast, TRF1 does not contribute significantly to the end protection functions of shelterin. We addressed the mechanism of TRF1 action using mouse conditional knockouts of BLM, TRF1, TPP1, and Rap1 in combination with expression of TRF1 and TIN2 mutants. The data establish that TRF1 binds BLM to facilitate lagging but not leading strand telomeric DNA synthesis. As the template for lagging strand telomeric DNA synthesis is the TTAGGG repeat strand, TRF1-bound BLM is likely required to remove secondary structures formed by these sequences. In addition, the data establish that TRF1 deploys TIN2 and the TPP1/POT1 heterodimers in shelterin to prevent ATR during telomere replication and repress the accompanying sister telomere associations. Thus, TRF1 uses two distinct mechanisms to promote replication of telomeric DNA and circumvent the consequences of replication stress. These data are relevant to the expression of CFSs and provide insights into TIN2, which is compromised in dyskeratosis congenita (DC) and related disorders.
authors.affiliation: Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York 10065, USA; Central European Institute of Technology, Masaryk University, Brno 625 00, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York 10065, USA;
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kibe
authors.affiliation: Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York 10065, USA;
authors.forename: Shaheen
authors.initials: S
authors.lastname: Kabir
authors.affiliation: Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York 10065, USA; delange@mail.rockefeller.edu.
authors.forename: Titia
authors.initials: T
authors.lastname: de Lange
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D055786:Gene Knockout Techniques; D018895:Microsatellite Repeats / Q000235:genetics*; D009154:Mutation; D011485:Protein Binding; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D057057:Serine Proteases / Q000235:genetics / Q000378:metabolism*; D000089804:Shelterin Complex; D015398:Signal Transduction; D016615:Telomere / Q000235:genetics*; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C544060:Acd protein, mouse; D004268:DNA-Binding Proteins; C507326:POT1 protein, mouse; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D035321:Telomeric Repeat Binding Protein 1; C499083:Tinf2 protein, mouse; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D057057:Serine Proteases; C097151:Bloom syndrome protein; D053484:RecQ Helicases
keywords: BLM; G quadruplex; TRF1; replication; shelterin; telomere