telomeric repeat binding protein 1


Summary: A ubiquitously expressed telomere-binding protein that is present at TELOMERES throughout the CELL CYCLE. It is a suppressor of telomere elongation and may be involved in stabilization of telomere length. It is structurally different from TELOMERIC REPEAT BINDING PROTEIN 2 in that it contains acidic N-terminal amino acid residues.

Top Publications

  1. Kim S, Davalos A, Heo S, Rodier F, Zou Y, Beausejour C, et al. Telomere dysfunction and cell survival: roles for distinct TIN2-containing complexes. J Cell Biol. 2008;181:447-60 pubmed publisher
    ..Our findings suggest that distinct TIN2 complexes exist and that TIN2-15C-sensitive subcomplexes are particularly important for cell survival in the absence of functional p53. ..
  2. Potts P, Yu H. The SMC5/6 complex maintains telomere length in ALT cancer cells through SUMOylation of telomere-binding proteins. Nat Struct Mol Biol. 2007;14:581-90 pubmed
    ..Thus, the SMC5/6 complex facilitates telomere HR and elongation in ALT cells by promoting APB formation through SUMOylation of telomere-binding proteins. ..
  3. Jiang W, Zhong Z, Henson J, Reddel R. Identification of candidate alternative lengthening of telomeres genes by methionine restriction and RNA interference. Oncogene. 2007;26:4635-47 pubmed
    ..Because of the close linkage between ALT-mediated telomere maintenance and ability to form APBs, the eight proteins identified by this screen as being required for APB formation are also likely to be required for the ALT mechanism. ..
  4. Nishikawa T, Nagadoi A, Yoshimura S, Aimoto S, Nishimura Y. Solution structure of the DNA-binding domain of human telomeric protein, hTRF1. Structure. 1998;6:1057-65 pubmed
    ..In addition to DNA recognition by the HTH variant, a flexible N-terminal arm of hTRF1 is likely to interact with DNA. ..
  5. Zhou X, Perrem K, Lu K. Role of Pin2/TRF1 in telomere maintenance and cell cycle control. J Cell Biochem. 2003;89:19-37 pubmed
    ..These results have led us to propose that Pin2/TRF1 functions as a key molecule in connecting telomere maintenance and cell cycle control. ..
  6. Yang S, Kim D, Lee J, Chun Y, Lee J, Kim Y, et al. Expression of the telomeric repeat binding factor gene NgTRF1 is closely coordinated with the cell division program in tobacco BY-2 suspension culture cells. J Biol Chem. 2003;278:21395-407 pubmed
    ..The possible physiological functions of NgTRF1 in tobacco cells are also discussed. ..
  7. Tsai R. Nucleolar modulation of TRF1: a dynamic way to regulate telomere and cell cycle by nucleostemin and GNL3L. Cell Cycle. 2009;8:2912-6 pubmed
    ..This manuscript extends the discussion on how this GNL3L-mediated TRF1 regulation creates a novel dynamic control on telomere and cell cycle, and extrapolates its evolutionary significance by contrasting the activities of NS and GNL3L. ..
  8. Zhu Q, Meng L, Hsu J, Lin T, Teishima J, Tsai R. GNL3L stabilizes the TRF1 complex and promotes mitotic transition. J Cell Biol. 2009;185:827-39 pubmed publisher
    ..Most importantly, the TRF1 protein-stabilizing activity of GNL3L mediates the mitotic increase of TRF1 protein and promotes the metaphase-to-anaphase transition. This work reveals novel aspects of TRF1 modulation by GNL3L. ..
  9. Netzer C, Rieger L, Brero A, Zhang C, Hinzke M, Kohlhase J, et al. SALL1, the gene mutated in Townes-Brocks syndrome, encodes a transcriptional repressor which interacts with TRF1/PIN2 and localizes to pericentromeric heterochromatin. Hum Mol Genet. 2001;10:3017-24 pubmed
    ..We have also provided new evidence that there is a close functional link between the centromeric and telomeric heterochromatin domains not only in Drosophila and yeast, but also in mammalian cells. ..

More Information


  1. Lin X, Gu J, Lu C, Spitz M, Wu X. Expression of telomere-associated genes as prognostic markers for overall survival in patients with non-small cell lung cancer. Clin Cancer Res. 2006;12:5720-5 pubmed
    ..21 versus 15.34 months, P < 0.0009). The expressions of TRF2 in tumor tissues were significantly correlated with tumor grades (P = 0.0114). RAP1 expression may be a useful biomarker of tumor progression and survival. ..
  2. Smogorzewska A, de Lange T. Regulation of telomerase by telomeric proteins. Annu Rev Biochem. 2004;73:177-208 pubmed
    ..Here we discuss the details of telomerase and its regulation by the telomere. ..
  3. Loayza D, de Lange T. POT1 as a terminal transducer of TRF1 telomere length control. Nature. 2003;423:1013-8 pubmed
  4. Ye J, Hockemeyer D, Krutchinsky A, Loayza D, Hooper S, Chait B, et al. POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev. 2004;18:1649-54 pubmed
    ..Reduction of PIP1 or POT1 levels with shRNAs led to telomere elongation, indicating that PIP1 contributes to telomere length control through recruitment of POT1. ..
  5. Ye J, Donigian J, Van Overbeek M, Loayza D, Luo Y, Krutchinsky A, et al. TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres. J Biol Chem. 2004;279:47264-71 pubmed
    ..The TIN2-mediated cooperative binding of TRF1 and TRF2 to telomeres has important implications for the mechanism of telomere length regulation and protection. ..
  6. Karamysheva Z, Surovtseva Y, Vespa L, Shakirov E, Shippen D. A C-terminal Myb extension domain defines a novel family of double-strand telomeric DNA-binding proteins in Arabidopsis. J Biol Chem. 2004;279:47799-807 pubmed
    ..Thus, Myb-ext is required for binding plant telomeric DNA and defines a novel class of proteins in Arabidopsis. ..
  7. García Aranda C, de Juan C, Díaz López A, Sánchez Pernaute A, Torres A, Diaz Rubio E, et al. Correlations of telomere length, telomerase activity, and telomeric-repeat binding factor 1 expression in colorectal carcinoma. Cancer. 2006;106:541-51 pubmed
    ..Conversely, colorectal tumors that over-expressed TRF1 demonstrated telomere shortening, and patients with those tumors had a better clinical course. ..
  8. Kim S, Kaminker P, Campisi J. TIN2, a new regulator of telomere length in human cells. Nat Genet. 1999;23:405-12 pubmed
    ..Our findings suggest that TRF1 is insufficient for control of telomere length in human cells, and that TIN2 is an essential mediator of TRF1 function. ..
  9. Bianchi A, Stansel R, Fairall L, Griffith J, Rhodes D, de Lange T. TRF1 binds a bipartite telomeric site with extreme spatial flexibility. EMBO J. 1999;18:5735-44 pubmed
    ..This unusual DNA binding mode is directly relevant to the proposed architectural role of TRF1. ..
  10. Sinha S, Bandyopadhyay S. Conformational fluctuations of a protein-DNA complex and the structure and ordering of water around it. J Chem Phys. 2011;135:245104 pubmed publisher
    ..Further, it is found that water molecules around the DNA are more structured with significantly higher density and ordering than that around the protein in the complex. ..
  11. Opresko P, Fan J, Danzy S, Wilson D, Bohr V. Oxidative damage in telomeric DNA disrupts recognition by TRF1 and TRF2. Nucleic Acids Res. 2005;33:1230-9 pubmed
    ..These studies indicate that oxidative DNA damage may exert deleterious effects on telomeres by disrupting the association of telomere-maintenance proteins TRF1 and TRF2. ..
  12. Walker J, Zhu X. Post-translational modifications of TRF1 and TRF2 and their roles in telomere maintenance. Mech Ageing Dev. 2012;133:421-34 pubmed publisher
    ..Here we review the post-translational modifications of TRF1 and TRF2 and discuss the mechanisms by which these modifications contribute to the function of these two proteins. ..
  13. Kim S, Beausejour C, Davalos A, Kaminker P, Heo S, Campisi J. TIN2 mediates functions of TRF2 at human telomeres. J Biol Chem. 2004;279:43799-804 pubmed
    ..TIN2 mutants defective in binding of TRF1 or TRF2 induce a DNA damage response and destabilize TRF1 and TRF2 at telomeres in human cells. Our findings suggest that the functions of TRF1 and TRF2 are linked by TIN2. ..
  14. Ohishi T, Hirota T, Tsuruo T, Seimiya H. TRF1 mediates mitotic abnormalities induced by Aurora-A overexpression. Cancer Res. 2010;70:2041-52 pubmed publisher
    ..By contrast, a TRF1 mutant that is not phosphorylatable by Aurora-A does not restore such Aurora-A-induced phenotype. We propose that TRF1 phosphorylation by excessive Aurora-A may provoke abnormal mitosis and chromosomal instability. ..
  15. Opresko P, Otterlei M, Graakjaer J, Bruheim P, Dawut L, Kølvraa S, et al. The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2. Mol Cell. 2004;14:763-74 pubmed
    ..The telomere binding proteins TRF1 and TRF2 limit digestion by WRN. We propose roles for WRN in dissociating telomeric structures in telomerase-deficient cells. ..
  16. Poulet A, Pisano S, Faivre Moskalenko C, Pei B, Tauran Y, Haftek Terreau Z, et al. The N-terminal domains of TRF1 and TRF2 regulate their ability to condense telomeric DNA. Nucleic Acids Res. 2012;40:2566-76 pubmed publisher
    ..Overall, these data suggest that the N-termini of TRF1 and TRF2 have evolved to finely regulate their ability to condense DNA. ..
  17. Griffith J, Comeau L, Rosenfield S, Stansel R, Bianchi A, Moss H, et al. Mammalian telomeres end in a large duplex loop. Cell. 1999;97:503-14 pubmed
    ..T loops may provide a general mechanism for the protection and replication of telomeres. ..
  18. McKerlie M, Lin S, Zhu X. ATM regulates proteasome-dependent subnuclear localization of TRF1, which is important for telomere maintenance. Nucleic Acids Res. 2012;40:3975-89 pubmed publisher
  19. Karlseder J. Telomere repeat binding factors: keeping the ends in check. Cancer Lett. 2003;194:189-97 pubmed
    ..Here it is discussed how mammalian telomeres differ from DNA breaks, and what methods they use to prevent checkpoint activation. ..
  20. Ballal R, Saha T, Fan S, Haddad B, Rosen E. BRCA1 localization to the telomere and its loss from the telomere in response to DNA damage. J Biol Chem. 2009;284:36083-98 pubmed publisher
    ..Our findings suggest that BRCA1 is recruited to the telomere in a Rad50-dependent manner and that BRCA1 may regulate telomere length and stability, in part through its presence at the telomere. ..
  21. Deng Z, Norseen J, Wiedmer A, Riethman H, Lieberman P. TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres. Mol Cell. 2009;35:403-13 pubmed publisher
    ..We conclude that TERRA facilitates TRF2 interaction with ORC and plays a central role in telomere structural maintenance and heterochromatin formation. ..
  22. Fouché N, Cesare A, Willcox S, Ozgur S, Compton S, Griffith J. The basic domain of TRF2 directs binding to DNA junctions irrespective of the presence of TTAGGG repeats. J Biol Chem. 2006;281:37486-95 pubmed
    ..Junction-specific binding would also allow TRF2 to stabilize a strand invasion structure that is thought to exist at the strand invasion site of the t-loop. ..
  23. Aragona M, de Divitiis O, La Torre D, Panetta S, D Avella D, Pontoriero A, et al. Immunohistochemical TRF1 expression in human primary intracranial tumors. Anticancer Res. 2001;21:2135-9 pubmed
    ..Although these preliminary observations need confirmation from larger studies, the TRF1 status in intracranial tumors might become of prognostic value. ..
  24. Yoshimura S, Maruyama H, Ishikawa F, Ohki R, Takeyasu K. Molecular mechanisms of DNA end-loop formation by TRF2. Genes Cells. 2004;9:205-18 pubmed
    ..TRF1 also bound to the telomeric DNA as a dimer, but did not mediate DNA loop formation by itself. These results provide a new insight into the molecular mechanism of DNA end-loop formation by TRFs. ..
  25. Meng L, Hsu J, Zhu Q, Lin T, Tsai R. Nucleostemin inhibits TRF1 dimerization and shortens its dynamic association with the telomere. J Cell Sci. 2011;124:3706-14 pubmed publisher
    ..Changing the relative amount of TRF1 monomers versus dimers in the nucleoplasm might affect the dynamic association of TRF1 with the telomere and the repair of damaged telomeres. ..
  26. Muñoz P, Blanco R, de Carcer G, Schoeftner S, Benetti R, Flores J, et al. TRF1 controls telomere length and mitotic fidelity in epithelial homeostasis. Mol Cell Biol. 2009;29:1608-25 pubmed publisher
    ..Together, these results demonstrate that TRF1, like TRF2, negatively regulates telomere length in vivo by controlling the action of the XPF nuclease at telomeres; in addition, TRF1 has a unique role in the mitotic spindle checkpoint. ..
  27. Kishi S, Lu K. A critical role for Pin2/TRF1 in ATM-dependent regulation. Inhibition of Pin2/TRF1 function complements telomere shortening, radiosensitivity, and the G(2)/M checkpoint defect of ataxia-telangiectasia cells. J Biol Chem. 2002;277:7420-9 pubmed
  28. O Connor M, Safari A, Xin H, Liu D, Songyang Z. A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. Proc Natl Acad Sci U S A. 2006;103:11874-9 pubmed
    ..Our results suggest that coordinated interactions among TPP1, TIN2, TRF1, and TRF2 may ensure robust assembly of the telosome, telomere targeting of its subunits, and, ultimately, regulated telomere maintenance. ..
  29. Broccoli D, Chong L, Oelmann S, Fernald A, Marziliano N, van Steensel B, et al. Comparison of the human and mouse genes encoding the telomeric protein, TRF1: chromosomal localization, expression and conserved protein domains. Hum Mol Genet. 1997;6:69-76 pubmed
    ..The TRF1 genes are not syntenic; the hTRF1 gene localized to human chromosome 8 band q13 while the mTRF1 gene localized to mouse chromosome 17 band E3. The data indicate that the genes for mammalian telomeric proteins evolve rapidly. ..
  30. van Steensel B, de Lange T. Control of telomere length by the human telomeric protein TRF1. Nature. 1997;385:740-3 pubmed
    ..As TRF1 does not detectably affect the expression of telomerase, we propose that the binding of TRF1 controls telomere length in cis by inhibiting the action of telomerase at the ends of individual telomeres. ..
  31. Bianchi A, Smith S, Chong L, Elias P, de Lange T. TRF1 is a dimer and bends telomeric DNA. EMBO J. 1997;16:1785-94 pubmed
    ..Furthermore, TRF1 was found to bend its telomeric site to an angle of -120 degrees. Since Rap1p similarly distorts telomeric DNA, we propose that DNA bending is important for the function of telomeres in yeast and mammals. ..
  32. Zhu Q, Yasumoto H, Tsai R. Nucleostemin delays cellular senescence and negatively regulates TRF1 protein stability. Mol Cell Biol. 2006;26:9279-90 pubmed
    ..This work demonstrates the roles of NS in establishing early embryogenesis and delaying cellular senescence of MEFs and reveals a mechanism of a NS-regulated degradation of TRF1. ..
  33. Koering C, Pollice A, Zibella M, Bauwens S, Puisieux A, Brunori M, et al. Human telomeric position effect is determined by chromosomal context and telomeric chromatin integrity. EMBO Rep. 2002;3:1055-61 pubmed
    ..Overall, position effects at human chromosome ends are dependent on a specific higher-order organization of the telomeric chromatin. The possible involvement of HP1 isoforms is discussed. ..
  34. Houghtaling B, Cuttonaro L, Chang W, Smith S. A dynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2. Curr Biol. 2004;14:1621-31 pubmed
    ..Our findings suggest a dynamic cross talk between TRF1 and TRF2 and provide a molecular mechanism for telomere length homeostasis by TRF2 in the absence of TRF1. ..
  35. Nishiyama A, Muraki K, Saito M, Ohsumi K, Kishimoto T, Ishikawa F. Cell-cycle-dependent Xenopus TRF1 recruitment to telomere chromatin regulated by Polo-like kinase. EMBO J. 2006;25:575-84 pubmed
    ..These results indicate that telomere chromatin is actively regulated by cell-cycle-dependent processes, and provide an insight for understanding how telomeres undergo DNA metabolisms during the cell cycle. ..
  36. Nishikawa T, Okamura H, Nagadoi A, Konig P, Rhodes D, Nishimura Y. Solution structure of a telomeric DNA complex of human TRF1. Structure. 2001;9:1237-51 pubmed
    ..Although TRF2 plays an important role in the t loop formation that protects the ends of telomeres, it is likely that the binding mode of TRF2 to double-stranded telomeric DNA is almost identical to that of TRF1. ..
  37. Court R, Chapman L, Fairall L, Rhodes D. How the human telomeric proteins TRF1 and TRF2 recognize telomeric DNA: a view from high-resolution crystal structures. EMBO Rep. 2005;6:39-45 pubmed
    ..The binding of the TRF2-Dbd to the DNA double helix shows no distortions that would account for the promotion of t-loops in which TRF2 has been implicated. ..
  38. Martinez P, Thanasoula M, Muñoz P, Liao C, Tejera A, McNees C, et al. Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice. Genes Dev. 2009;23:2060-75 pubmed publisher
  39. Seimiya H, Smith S. The telomeric poly(ADP-ribose) polymerase, tankyrase 1, contains multiple binding sites for telomeric repeat binding factor 1 (TRF1) and a novel acceptor, 182-kDa tankyrase-binding protein (TAB182). J Biol Chem. 2002;277:14116-26 pubmed
    ..We discuss potential roles for tankyrase 1-mediated higher order complexes at telomeres and at other subcellular sites. ..
  40. Karlseder J, Kachatrian L, Takai H, Mercer K, Hingorani S, Jacks T, et al. Targeted deletion reveals an essential function for the telomere length regulator Trf1. Mol Cell Biol. 2003;23:6533-41 pubmed
    ..These data suggest that murine Trf1 has an essential function that is independent of telomere length regulation. ..
  41. Xu Y, Lan J, Zhu Y. [Important role of Ser 219 phosphorylation of TRF1 in regulation of cell cycle]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2007;36:325-30 pubmed
    ..05). The protein level of ATM was increased when overexpression the wide type or mutants. The Ser 219 phosphorylation of TRF1 by ATM could result in cell cycle arrest in G2/M, which is related to overexpression of TRF1. ..
  42. Schoeftner S, Blasco M. Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol. 2008;10:228-36 pubmed
    ..Our results indicate that TelRNAs are novel components of mammalian telomeres, which are anticipated to be fundamental for understanding telomere biology and telomere-related diseases, such as cancer and ageing. ..
  43. Smith S, de Lange T. Tankyrase promotes telomere elongation in human cells. Curr Biol. 2000;10:1299-302 pubmed
    ..Our results indicate that tankyrase can induce telomere elongation in human cells. We propose that tankyrase-mediated ADP-ribosylation of TRF1 opens the telomeric complex, allowing access to telomerase. ..
  44. Okamoto K, Iwano T, Tachibana M, Shinkai Y. Distinct roles of TRF1 in the regulation of telomere structure and lengthening. J Biol Chem. 2008;283:23981-8 pubmed publisher
  45. Nakanishi K, Kawai T, Kumaki F, Hiroi S, Mukai M, Ikeda E, et al. Expression of mRNAs for telomeric repeat binding factor (TRF)-1 and TRF2 in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Clin Cancer Res. 2003;9:1105-11 pubmed
    ..These results are consistent with (but are not enough to confirm) the idea that high-grade AAH is closely related to BAC. ..
  46. Ye J, de Lange T. TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nat Genet. 2004;36:618-23 pubmed
    ..These data identify TIN2 as a PARP modulator in the TRF1 complex and can explain how TIN2 contributes to the regulation of telomere length. ..
  47. Galati A, Rossetti L, Pisano S, Chapman L, Rhodes D, Savino M, et al. The human telomeric protein TRF1 specifically recognizes nucleosomal binding sites and alters nucleosome structure. J Mol Biol. 2006;360:377-85 pubmed
    ..These results indicate that nucleosomes contribute to the establishment of a telomeric capping complex, whose structure and dynamics can be modulated by the binding of telomeric factors. ..
  48. Ohyashiki J, Hayashi S, Yahata N, Iwama H, Ando K, Tauchi T, et al. Impaired telomere regulation mechanism by TRF1 (telomere-binding protein), but not TRF2 expression, in acute leukemia cells. Int J Oncol. 2001;18:593-8 pubmed
  49. Matsutani N, Yokozaki H, Tahara H, Kuniyasu H, Haruma K, Chayama K, et al. Expression of telomeric repeat binding factor 1 and 2 and TRF1-interacting nuclear protein 2 in human gastric carcinomas. Int J Oncol. 2001;19:507-12 pubmed
  50. Yang S, Kim S, Kim W. Perturbation of NgTRF1 expression induces apoptosis-like cell death in tobacco BY-2 cells and implicates NgTRF1 in the control of telomere length and stability. Plant Cell. 2004;16:3370-85 pubmed
    ..We further suggest that the structural stability of telomeres, in addition to length maintenance, is essential for their function and for the immortality of BY-2 cells. ..
  51. Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer M, Schnapp G, et al. Control of human telomere length by TRF1 and TRF2. Mol Cell Biol. 2000;20:1659-68 pubmed
  52. Wu G, Lee W, Chen P. NBS1 and TRF1 colocalize at promyelocytic leukemia bodies during late S/G2 phases in immortalized telomerase-negative cells. Implication of NBS1 in alternative lengthening of telomeres. J Biol Chem. 2000;275:30618-22 pubmed
    ..These results suggest that NBS1 may be involved in alternative lengthening of telomeres in telomerase-negative immortalized cells. ..
  53. Wu G, Jiang X, Lee W, Chen P. Assembly of functional ALT-associated promyelocytic leukemia bodies requires Nijmegen Breakage Syndrome 1. Cancer Res. 2003;63:2589-95 pubmed
    ..Taken together, these results support a model in which NBS1 has a vital role in the assembly of APBs, which function to maintain telomeres in human ALT cells. ..