telomeric repeat binding protein 2

Summary

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 1 in that it contains basic N-terminal amino acid residues.

Top Publications

  1. Broccoli D, Smogorzewska A, Chong L, de Lange T. Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. Nat Genet. 1997;17:231-5 pubmed
    ..Because TRF1 and TRF2 showed significant differences, we suggest that these factors have distinct functions at telomeres. ..
  2. Hu H, Zhang Y, Zou M, Yang S, Liang X. Expression of TRF1, TRF2, TIN2, TERT, KU70, and BRCA1 proteins is associated with telomere shortening and may contribute to multistage carcinogenesis of gastric cancer. J Cancer Res Clin Oncol. 2010;136:1407-14 pubmed publisher
    ..These findings offer new insight into the mechanism of carcinogenesis in gastric cancer. ..
  3. Bailey S, Cornforth M, Kurimasa A, Chen D, Goodwin E. Strand-specific postreplicative processing of mammalian telomeres. Science. 2001;293:2462-5 pubmed
    ..These results demonstrate a crucial difference in postreplicative processing of telomeres that is linked to their mode of replication. ..
  4. Takai H, Smogorzewska A, de Lange T. DNA damage foci at dysfunctional telomeres. Curr Biol. 2003;13:1549-56 pubmed
    ..Furthermore, induction of TIFs through TRF2 inhibition provides an opportunity to study the DNA damage response within the context of well-defined, physically marked lesions. ..
  5. Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov J, et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol. 2012;14:355-65 pubmed publisher
    ..We propose that linear genomes are not uniformly reparable and that telomeric DNA tracts, if damaged, are irreparable and trigger persistent DDR and cellular senescence. ..
  6. Kim H, Lee O, Xin H, Chen L, Qin J, Chae H, et al. TRF2 functions as a protein hub and regulates telomere maintenance by recognizing specific peptide motifs. Nat Struct Mol Biol. 2009;16:372-9 pubmed publisher
    ..Our findings indicate that an array of TRF2 molecules functions as a protein hub and regulates telomeres by recruiting different signaling molecules via a linear sequence code. ..
  7. Pedroso I, Hayward W, Fletcher T. The effect of the TRF2 N-terminal and TRFH regions on telomeric G-quadruplex structures. Nucleic Acids Res. 2009;37:1541-54 pubmed publisher
    ..This study is the first analysis of the effects of TRF2 domains on G-quadruplex structures and has implications for the role of G-quadruplexes and TRF2 in the formation of t-loops. ..
  8. Gomez D, O Donohue M, Wenner T, Douarre C, Macadré J, Koebel P, et al. The G-quadruplex ligand telomestatin inhibits POT1 binding to telomeric sequences in vitro and induces GFP-POT1 dissociation from telomeres in human cells. Cancer Res. 2006;66:6908-12 pubmed
    ..Thus, we propose that G-quadruplex stabilization at telomeric G-overhang inactivates POT1 telomeric function, generating a telomere dysfunction in which chromosome ends are no longer properly protected. ..
  9. Nora G, Buncher N, Opresko P. Telomeric protein TRF2 protects Holliday junctions with telomeric arms from displacement by the Werner syndrome helicase. Nucleic Acids Res. 2010;38:3984-98 pubmed publisher
    ..Our biochemical study provides a mechanistic basis for the cellular findings that TRF2 regulates WRN activity at telomeres. ..

More Information

Publications62

  1. Biroccio A, Rizzo A, Elli R, Koering C, Belleville A, Benassi B, et al. TRF2 inhibition triggers apoptosis and reduces tumourigenicity of human melanoma cells. Eur J Cancer. 2006;42:1881-8 pubmed
    ..They further suggest that a basal level of telomere instability favours an efficient response to TRF2 inhibition and that a combined anti-TRF2 and G4-ligand therapy would have synergistic inhibitory effects on tumour cell growth. ..
  2. Yoo H, Chung I. Requirement of DDX39 DEAD box RNA helicase for genome integrity and telomere protection. Aging Cell. 2011;10:557-71 pubmed publisher
  3. Smogorzewska A, Karlseder J, Holtgreve Grez H, Jauch A, de Lange T. DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2. Curr Biol. 2002;12:1635-44 pubmed
    ..The involvement of NHEJ in telomere fusions is paradoxical since the NHEJ factors Ku70/80 and DNA-PKcs are present at telomeres and protect chromosome ends from fusion. ..
  4. Zhu X, Kuster B, Mann M, Petrini J, de Lange T. Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nat Genet. 2000;25:347-52 pubmed
    ..Instead, we propose that the MRE11 complex functions at telomeres, possibly by modulating t-loop formation. ..
  5. Song K, Jung D, Jung Y, Lee S, Lee I. Interaction of human Ku70 with TRF2. FEBS Lett. 2000;481:81-5 pubmed
    ..This interaction was confirmed using bacterial fusion proteins and co-immunoprecipitations from eukaryotic cells overexpressing TRF2. The transfected TFR2 colocalized with Ku70. ..
  6. Sfeir A, de Lange T. Removal of shelterin reveals the telomere end-protection problem. Science. 2012;336:593-7 pubmed publisher
  7. Bombarde O, Boby C, Gomez D, Frit P, Giraud Panis M, Gilson E, et al. TRF2/RAP1 and DNA-PK mediate a double protection against joining at telomeric ends. EMBO J. 2010;29:1573-84 pubmed publisher
    ..Thus, telomeres are protected against EJ by a lock with two bolts. These results account for observations with mammalian models and underline the importance of alternative non-classical EJ pathways for telomere fusions in cells. ..
  8. Baker A, Fu Q, Hayward W, Lindsay S, Fletcher T. The Myb/SANT domain of the telomere-binding protein TRF2 alters chromatin structure. Nucleic Acids Res. 2009;37:5019-31 pubmed publisher
    ..The TRF2 DBD had less effect on histone-free DNA structure and did not stimulate the t-loop reaction with this substrate, highlighting the influence of chromatin structure on the activities of DNA-binding proteins. ..
  9. Wu Y, Mitchell T, Zhu X. Human XPF controls TRF2 and telomere length maintenance through distinctive mechanisms. Mech Ageing Dev. 2008;129:602-10 pubmed publisher
    ..Our results further imply that TRF2 association with telomeres may be deregulated in cells derived from XPF patients. ..
  10. Stagno d Alcontres M, Mendez Bermudez A, Foxon J, Royle N, Salomoni P. Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA. J Cell Biol. 2007;179:855-67 pubmed
    ..Finally, we find a substantial loss of telomeric DNA upon stable TRF2 knockdown in ALT cells. Overall, we provide insight into the functional consequences of shelterin alterations in ALT cells...
  11. Hsu C, Ko J, Shai S, Lee L. Modulation of telomere shelterin by TRF1 [corrected] and TRF2 interacts with telomerase to maintain the telomere length in non-small cell lung cancer. Lung Cancer. 2007;58:310-6 pubmed
    ..However, when the TRF length reaches a critical level, changing the telomere shelterin by persistent expression of the TRF2, which in combination with telomerase activation reverses the telomere shortening. ..
  12. Amiard S, Doudeau M, Pinte S, Poulet A, Lenain C, Faivre Moskalenko C, et al. A topological mechanism for TRF2-enhanced strand invasion. Nat Struct Mol Biol. 2007;14:147-54 pubmed
    ..Implications of this topological model in t-loop formation and telomere homeostasis are discussed. ..
  13. Fairall L, Chapman L, Moss H, de Lange T, Rhodes D. Structure of the TRFH dimerization domain of the human telomeric proteins TRF1 and TRF2. Mol Cell. 2001;8:351-61 pubmed
    ..A possible structural homology between the TRFH domain of fission yeast telomeric protein Taz1 with those of the vertebrate TRFs is suggested. ..
  14. Van Overbeek M, de Lange T. Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase. Curr Biol. 2006;16:1295-302 pubmed
    ..We propose that the Artemis-like nuclease Apollo is a shelterin accessory factor required for the protection of telomeres during or after their replication. ..
  15. Ancelin K, Brunori M, Bauwens S, Koering C, Brun C, Ricoul M, et al. Targeting assay to study the cis functions of human telomeric proteins: evidence for inhibition of telomerase by TRF1 and for activation of telomere degradation by TRF2. Mol Cell Biol. 2002;22:3474-87 pubmed
    ..In these cells, overexpression of full-length TRF2 leads to an increased rate of telomere shortening. ..
  16. Ohki R, Ishikawa F. Telomere-bound TRF1 and TRF2 stall the replication fork at telomeric repeats. Nucleic Acids Res. 2004;32:1627-37 pubmed
    ..The results suggest that TRF1 and TRF2 exert inhibitory effects on replication fork progression. ..
  17. Zhu X, Niedernhofer L, Kuster B, Mann M, Hoeijmakers J, de Lange T. ERCC1/XPF removes the 3' overhang from uncapped telomeres and represses formation of telomeric DNA-containing double minute chromosomes. Mol Cell. 2003;12:1489-98 pubmed
  18. Sarthy J, Bae N, Scrafford J, Baumann P. Human RAP1 inhibits non-homologous end joining at telomeres. EMBO J. 2009;28:3390-9 pubmed publisher
    ..These results provide the first evidence that hRAP1 inhibits NHEJ at mammalian telomeres and identify hRAP1 as a mediator of genome stability. ..
  19. Lillard Wetherell K, Machwe A, Langland G, Combs K, Behbehani G, Schonberg S, et al. Association and regulation of the BLM helicase by the telomere proteins TRF1 and TRF2. Hum Mol Genet. 2004;13:1919-32 pubmed
    ..These data suggest a function for BLM in recombination-mediated telomere lengthening and support a model for the coordinated regulation of BLM activity at telomeres by TRF1 and TRF2. ..
  20. Takai K, Hooper S, Blackwood S, Gandhi R, de Lange T. In vivo stoichiometry of shelterin components. J Biol Chem. 2010;285:1457-67 pubmed publisher
    ..Finally, we report that a 10-fold reduction in TRF2 affects the regulation of telomere length but not the protection of telomeres in tumor cell lines. ..
  21. Baker A, Fu Q, Hayward W, Victoria S, Pedroso I, Lindsay S, et al. The telomere binding protein TRF2 induces chromatin compaction. PLoS ONE. 2011;6:e19124 pubmed publisher
    ..Our data suggest that nucleosomal chromatin has the ability to facilitate this activity of TRF2 which is thought to be involved in stabilizing looped telomere structures. ..
  22. Deng Z, Atanasiu C, Burg J, Broccoli D, Lieberman P. Telomere repeat binding factors TRF1, TRF2, and hRAP1 modulate replication of Epstein-Barr virus OriP. J Virol. 2003;77:11992-2001 pubmed
    ..These results indicate that TRF2 and hRap1 promote, while TRF1 antagonizes, OriP-dependent DNA replication and suggest that these telomeric factors contribute to the establishment of replication competence at OriP. ..
  23. Bradshaw P, Stavropoulos D, Meyn M. Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage. Nat Genet. 2005;37:193-7 pubmed
    ..Our results implicate TRF2 in an initial stage of DSB recognition and processing that occurs before association of ATM with DSBs and activation of the ATM-dependent DSB response network. ..
  24. Simonet T, Zaragosi L, Philippe C, Lebrigand K, Schouteden C, Augereau A, et al. The human TTAGGG repeat factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats. Cell Res. 2011;21:1028-38 pubmed publisher
    ..We propose that TRF1 and TRF2 couple the functional state of telomeres to the long-range organization of chromosomes and gene regulation networks by binding to extratelomeric sequences. ..
  25. Zhang D, Penttila T, Morris P, Teichmann M, Roeder R. Spermiogenesis deficiency in mice lacking the Trf2 gene. Science. 2001;292:1153-5 pubmed
    ..We speculate that mammals may have evolved more specialized TRF2 functions in the testis that involve transcriptional regulation of genes essential for spermiogenesis. ..
  26. Yang D, Xiong Y, Kim H, He Q, Li Y, Chen R, et al. Human telomeric proteins occupy selective interstitial sites. Cell Res. 2011;21:1013-27 pubmed publisher
    ..Our results indicate that human telomeric proteins could occupy a limited number of interstitial sites and regulate gene transcription. ..
  27. Xu L, Blackburn E. Human Rif1 protein binds aberrant telomeres and aligns along anaphase midzone microtubules. J Cell Biol. 2004;167:819-30 pubmed
    ..In telophase, hRif1 localized to chromosomes, and in interphase, it was intranuclear. These results define a novel subcellular localization behavior for hRif1 during the cell cycle. ..
  28. Richter T, Saretzki G, Nelson G, Melcher M, Olijslagers S, von Zglinicki T. TRF2 overexpression diminishes repair of telomeric single-strand breaks and accelerates telomere shortening in human fibroblasts. Mech Ageing Dev. 2007;128:340-5 pubmed
  29. Yanez G, Khan S, Locovei A, Pedroso I, Fletcher T. DNA structure-dependent recruitment of telomeric proteins to single-stranded/double-stranded DNA junctions. Biochem Biophys Res Commun. 2005;328:49-56 pubmed
    ..This suggests that an intramolecular G-quadruplex has the potential to disrupt certain telomeric assemblies, but efficient recruitment of appropriate DNA repair proteins provides the means to overcome this obstacle. ..
  30. Li G, Eller M, Firoozabadi R, Gilchrest B. Evidence that exposure of the telomere 3' overhang sequence induces senescence. Proc Natl Acad Sci U S A. 2003;100:527-31 pubmed
    ..We further demonstrate that these responses can be induced by treatment with oligonucleotides homologous to the overhang in the absence of telomere disruption, a phenomenon of potential therapeutic importance. ..
  31. Tanaka H, Mendonca M, Bradshaw P, Hoelz D, Malkas L, Meyn M, et al. DNA damage-induced phosphorylation of the human telomere-associated protein TRF2. Proc Natl Acad Sci U S A. 2005;102:15539-44 pubmed
  32. Wu P, Van Overbeek M, Rooney S, de Lange T. Apollo contributes to G overhang maintenance and protects leading-end telomeres. Mol Cell. 2010;39:606-17 pubmed publisher
    ..These data establish that the telomeric overhang is required for the protection of telomeres from the DNA damage response. ..
  33. Li B, Oestreich S, de Lange T. Identification of human Rap1: implications for telomere evolution. Cell. 2000;101:471-83 pubmed
    ..We propose that budding yeast preserved Rap1 at telomeres but lost the TRF component, possibly concomitant with a change in the telomeric repeat sequence. ..
  34. Dimitrova N, de Lange T. Cell cycle-dependent role of MRN at dysfunctional telomeres: ATM signaling-dependent induction of nonhomologous end joining (NHEJ) in G1 and resection-mediated inhibition of NHEJ in G2. Mol Cell Biol. 2009;29:5552-63 pubmed publisher
    ..Thus, the role of MRN at dysfunctional telomeres is multifaceted, involving both repression of NHEJ in G(2) through end resection and induction of NHEJ in G(1) through ATM-dependent signaling...
  35. Rai R, Zheng H, He H, Luo Y, Multani A, Carpenter P, et al. The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres. EMBO J. 2010;29:2598-610 pubmed publisher
    ..Our results reveal that telomeres engage distinct DNA repair pathways depending on how they are rendered dysfunctional, and that A-NHEJ is a major pathway to process dysfunctional telomeres. ..
  36. Fujita K, Horikawa I, Mondal A, Jenkins L, Appella E, Vojtesek B, et al. Positive feedback between p53 and TRF2 during telomere-damage signalling and cellular senescence. Nat Cell Biol. 2010;12:1205-12 pubmed publisher
    ..This study reveals that p53, a downstream effector of telomere-initiated damage signalling, also functions upstream of the shelterin complex. ..
  37. Zhang P, Furukawa K, Opresko P, Xu X, Bohr V, Mattson M. TRF2 dysfunction elicits DNA damage responses associated with senescence in proliferating neural cells and differentiation of neurons. J Neurochem. 2006;97:567-81 pubmed
  38. Tsumuki H, Nakazawa M, Hasunuma T, Kobata T, Kato T, Uchida A, et al. Infection of synoviocytes with HTLV-I induces telomerase activity. Rheumatol Int. 2001;20:175-9 pubmed
    ..These findings suggest that telomerase activation in synoviocytes has an important role in upregulated proliferative activity of HAAP synoviocytes. ..
  39. Hanaoka S, Nagadoi A, Nishimura Y. Comparison between TRF2 and TRF1 of their telomeric DNA-bound structures and DNA-binding activities. Protein Sci. 2005;14:119-30 pubmed
    ..Based on the structural differences of both domains, we created several mutants of the DNA-binding domain of TRF2 with stronger binding activities compared to the wild-type TRF2. ..
  40. Celli G, de Lange T. DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion. Nat Cell Biol. 2005;7:712-8 pubmed
    ..Thus, activation of the ATM kinase pathway at chromosome ends does not require overhang degradation or other overt DNA processing. ..
  41. de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005;19:2100-10 pubmed
    ..Six shelterin subunits: TRF1, TRF2, TIN2, Rap1, TPP1, and POT1. ..
  42. Konishi A, de Lange T. Cell cycle control of telomere protection and NHEJ revealed by a ts mutation in the DNA-binding domain of TRF2. Genes Dev. 2008;22:1221-30 pubmed publisher
    ..In contrast, the processing of dysfunctional telomeres by NHEJ occurred primarily in G1, being repressed in S/G2 in a cyclin-dependent kinase (CDK)-dependent manner. ..
  43. Celli G, Denchi E, de Lange T. Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination. Nat Cell Biol. 2006;8:885-90 pubmed
    ..Therefore, Ku- and TRF2-mediated repression of homologous recombination is an important aspect of telomere protection. ..
  44. Atanasiu C, Deng Z, Wiedmer A, Norseen J, Lieberman P. ORC binding to TRF2 stimulates OriP replication. EMBO Rep. 2006;7:716-21 pubmed
    ..These results support a model in which TRF2 stimulates OriP replication activity by direct binding with ORC subunits. ..
  45. Muñoz P, Blanco R, Blasco M. Role of the TRF2 telomeric protein in cancer and ageing. Cell Cycle. 2006;5:718-21 pubmed
    ..K5-TRF2 mice represent a new tool to understand the consequences of critical telomere shortening a telomerase-proficient genetic background, more closely resembling human cancer and aging pathologies. ..
  46. Buscemi G, Zannini L, Fontanella E, Lecis D, Lisanti S, Delia D. The shelterin protein TRF2 inhibits Chk2 activity at telomeres in the absence of DNA damage. Curr Biol. 2009;19:874-9 pubmed publisher
  47. Li B, Espinal A, Cross G. Trypanosome telomeres are protected by a homologue of mammalian TRF2. Mol Cell Biol. 2005;25:5011-21 pubmed
    ..This work also establishes T. brucei as an attractive model for telomere biology. ..
  48. Oh B, Kim Y, Park C, Park Y. Up-regulation of telomere-binding proteins, TRF1, TRF2, and TIN2 is related to telomere shortening during human multistep hepatocarcinogenesis. Am J Pathol. 2005;166:73-80 pubmed
    ..001). This was more evident in DNs and DNs with HCC foci. In conclusion, TRF1, TRF2, and TIN2 might be involved in multistep hepatocarcinogenesis by playing crucial roles in telomere shortening. ..
  49. Wu P, de Lange T. No overt nucleosome eviction at deprotected telomeres. Mol Cell Biol. 2008;28:5724-35 pubmed publisher
    ..We conclude that ATM signaling, ATR signaling, NHEJ, and HR at deprotected telomeres can take place in the absence of overt nucleosome eviction. ..
  50. Liu D, O Connor M, Qin J, Songyang Z. Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J Biol Chem. 2004;279:51338-42 pubmed
    ..These results help to unify previous observations and suggest that telomere maintenance depends on the multi-subunit telosome. ..
  51. Baumann P, Podell E, Cech T. Human Pot1 (protection of telomeres) protein: cytolocalization, gene structure, and alternative splicing. Mol Cell Biol. 2002;22:8079-87 pubmed
    ..In addition to these splice variants, the Pot1 family is expanded by the identification of six more genes from diverse species. Pot1-like proteins have now been found in plants, animals, yeasts, and microsporidia. ..
  52. Khan S, Yanez G, Seldeen K, Wang H, Lindsay S, Fletcher T. Interactions of TRF2 with model telomeric ends. Biochem Biophys Res Commun. 2007;363:44-50 pubmed
    ..We suggest that T-loop formation at telomere ends involves TRF2 binding to the G-strand overhang and oligomerization through both the known TRFH domain and the linker region. ..
  53. Benetti R, Schoeftner S, Muñoz P, Blasco M. Role of TRF2 in the assembly of telomeric chromatin. Cell Cycle. 2008;7:3461-8 pubmed
    ..Telomere shortening in K5TRF2 mice is also accompanied by decreased abundance of telomeric transcripts. Together, these findings indicate a previously unnoticed role for TRF2 in the assembly of telomeric chromatin. ..