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Gene Review

TERF2  -  telomeric repeat binding factor 2

Homo sapiens

Synonyms: TRBF2, TRF2, TTAGGG repeat-binding factor 2, Telomeric DNA-binding protein, Telomeric repeat-binding factor 2
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Disease relevance of TERF2


High impact information on TERF2

  • Furthermore, overexpression of TRF2 inhibits DSB-induced phosphorylation of ATM signaling targets [5].
  • These same networks tolerate telomeres, in part because the protein TRF2 prevents recognition of telomeric ends as DSBs by facilitating their organization into T loops [5].
  • Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage [5].
  • We now show that TRF2 associates with photo-induced DSBs in nontelomeric DNA in human fibroblasts within 2 s of irradiation [5].
  • These findings suggest that TRF2 provides a crucial link between telomere function and ultraviolet-induced damage repair, whose alteration underlies genomic instability, cancer and aging [6].

Chemical compound and disease context of TERF2


Biological context of TERF2


Anatomical context of TERF2

  • Human TATA-binding protein-related factor-2 (hTRF2) stably associates with hTFIIA in HeLa cells [13].
  • In vivo TRF2-GFP and immuno-staining studies in muntjac cell lines revealed telomeric TRF2 localization, while deletion of the DNA binding domain abrogated this localization, suggesting muntjac TRF2 represents a functional telomere protein [10].
  • RESULTS: TRF1, TRF2 and TIN2 mRNAs were significantly down-regulated in cancers compared to non-cancerous mucosa [14].
  • Next, the down-regulation of hTERT transcription by Tax in HTLV-1 transformed or in Tax-expressing T lymphocytes is found to correlate with a significant increase of TRF2 and/or Pot1 mRNAs [15].
  • TRF1 and TRF2 were also studied using an immunohistochemical method to determine the frequency of these factors in cell nuclei [16].

Associations of TERF2 with chemical compounds


Physical interactions of TERF2

  • The MRN complex is also involved in telomere maintenance, as demonstrated by the shortened telomeres in NBS primary human fibroblasts and the association of NBS1 with the telomere-binding protein TRF2 [21].
  • We show here that TIN2 also interacts with TRF2 in vitro and in yeast and mammalian cells [22].
  • Here, we show that fusions of hTERT containing different mutations in this domain to the telomere binding protein hTRF2 redirected the mutated hTERT to telomeres and rescued its in vivo functions [23].
  • The treatment of human EcR293 cells by telomestatin induces a dramatic and rapid delocalization of POT1 from its normal telomere sites but does not affect the telomere localization of the double-stranded telomere-binding protein TRF2 [24].
  • It involves a stretch of at least 25 amino acids at the C-terminus of hRap1 that interact with TRF2 [25].

Co-localisations of TERF2

  • In human cells, we report that WRN co-localizes and physically interacts with the critical telomere maintenance protein TRF2 [26].
  • BLM co-localizes with TRF2 in foci actively synthesizing DNA during late S and G2/M; co-localization increases in late S and G2/M when ALT is thought to occur [27].

Regulatory relationships of TERF2


Other interactions of TERF2

  • However, while scRap1 binds telomeric DNA directly, hRap1 is recruited to telomeres by TRF2 [32].
  • 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 [5].
  • Here we show by nanoelectrospray tandem mass spectrometry that RAD50 protein is present in TRF2 immunocomplexes [33].
  • Thus, in less than 50 PDs, the length of telomeres increased 3-8-fold beyond physiological size, while telomere-bound TRF1 and TRF2 increased proportionally to telomere length [34].
  • Up-regulation of telomere-binding proteins, TRF1, TRF2, and TIN2 is related to telomere shortening during human multistep hepatocarcinogenesis [35].
  • Our genome-wide target analysis revealed phosphatase nuclear targeting subunit (PNUTS) and microcephalin 1 (MCPH1) as previously unreported telomere-associated proteins that directly interact with TRF2 via the [Y/F]XL motif [36].

Analytical, diagnostic and therapeutic context of TERF2


  1. Expression of mRNAs for telomeric repeat binding factor (TRF)-1 and TRF2 in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Nakanishi, K., Kawai, T., Kumaki, F., Hiroi, S., Mukai, M., Ikeda, E., Koering, C.E., Gilson, E. Clin. Cancer Res. (2003) [Pubmed]
  2. Genetic variation in telomeric repeat binding factors 1 and 2 in aplastic anemia. Savage, S.A., Calado, R.T., Xin, Z.T., Ly, H., Young, N.S., Chanock, S.J. Exp. Hematol. (2006) [Pubmed]
  3. TERF2-XPF: caught in the middle; beginnings from the end. McDaniel, L.D., Schultz, R.A., Friedberg, E.C. DNA Repair (Amst.) (2006) [Pubmed]
  4. Telomerase activity in B-cell non-Hodgkin lymphomas is regulated by hTERT transcription and correlated with telomere-binding protein expression but uncoupled from proliferation. Klapper, W., Krams, M., Qian, W., Janssen, D., Parwaresch, R. Br. J. Cancer (2003) [Pubmed]
  5. Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage. Bradshaw, P.S., Stavropoulos, D.J., Meyn, M.S. Nat. Genet. (2005) [Pubmed]
  6. XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer. Muñoz, P., Blanco, R., Flores, J.M., Blasco, M.A. Nat. Genet. (2005) [Pubmed]
  7. Up-regulation of telomere-binding TRF1, TRF2 related to reactive oxygen species induced by As(2)O(3) in MGC-803 cells. Zhang, Y., Cao, E.H., Qin, J.F. Eur. J. Pharmacol. (2005) [Pubmed]
  8. TRF2 is in neuroglial cytoplasm and induces neurite-like processes. Jung, Y., Lee, S., Bang, S., Kim, S., Choi, K., Lee, C., Lee, S.G., Kim, C.J., Song, K., Lee, I. FEBS Lett. (2004) [Pubmed]
  9. DNA damage-induced cell cycle checkpoints involve both p53-dependent and -independent pathways: role of telomere repeat binding factor 2. Narayan, S., Jaiswal, A.S., Multani, A.S., Pathak, S. Br. J. Cancer (2001) [Pubmed]
  10. Characterization of the telomere complex, TERF1 and TERF2 genes in muntjac species with fusion karyotypes. Hartmann, N., Scherthan, H. Exp. Cell Res. (2005) [Pubmed]
  11. Assignment of TERF1 to chicken chromosome 2q32 and TERF2 to chicken microchromosome 11 by fluorescence in situ hybridization. Fillon, V., Critcher, R., Baird, K.M., Konrad, J.P., Vignal, A., Farr, C.J. Cytogenet. Cell Genet. (2001) [Pubmed]
  12. Chromosomal sublocalization of the transcribed human telomere repeat binding factor 2 gene and comparative mapping in the mouse. Sakaguchi, A.Y., Padalecki, S.S., Mattern, V., Rodriguez, A., Leach, R.J., McGill, J.R., Chavez, M., Giambernardi, T.A. Somat. Cell Mol. Genet. (1998) [Pubmed]
  13. Human TATA-binding protein-related factor-2 (hTRF2) stably associates with hTFIIA in HeLa cells. Teichmann, M., Wang, Z., Martinez, E., Tjernberg, A., Zhang, D., Vollmer, F., Chait, B.T., Roeder, R.G. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  14. Down-regulation of TRF1, TRF2 and TIN2 genes is important to maintain telomeric DNA for gastric cancers. Yamada, M., Tsuji, N., Nakamura, M., Moriai, R., Kobayashi, D., Yagihashi, A., Watanabe, N. Anticancer Res. (2002) [Pubmed]
  15. A balanced transcription between telomerase and the telomeric DNA-binding proteins TRF1, TRF2 and Pot1 in resting, activated, HTLV-1-transformed and Tax-expressing human T lymphocytes. Escoffier, E., Rezza, A., Roborel de Climens, A., Belleville, A., Gazzolo, L., Gilson, E., Duc Dodon, M. Retrovirology (2005) [Pubmed]
  16. Correlation between telomerase activity and telomeric-repeat binding factors in gastric cancer. Miyachi, K., Fujita, M., Tanaka, N., Sasaki, K., Sunagawa, M. J. Exp. Clin. Cancer Res. (2002) [Pubmed]
  17. Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase. van Overbeek, M., de Lange, T. Curr. Biol. (2006) [Pubmed]
  18. Nucleolar localization of the human telomeric repeat binding factor 2 (TRF2). Zhang, S., Hemmerich, P., Grosse, F. J. Cell. Sci. (2004) [Pubmed]
  19. Comparison between TRF2 and TRF1 of their telomeric DNA-bound structures and DNA-binding activities. Hanaoka, S., Nagadoi, A., Nishimura, Y. Protein Sci. (2005) [Pubmed]
  20. DNA structure-dependent recruitment of telomeric proteins to single-stranded/double-stranded DNA junctions. Yanez, G.H., Khan, S.J., Locovei, A.M., Pedroso, I.M., Fletcher, T.M. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  21. Telomere instability in a human tumor cell line expressing NBS1 with mutations at sites phosphorylated by ATM. Bai, Y., Murnane, J.P. Mol. Cancer Res. (2003) [Pubmed]
  22. TIN2 mediates functions of TRF2 at human telomeres. Kim, S.H., Beausejour, C., Davalos, A.R., Kaminker, P., Heo, S.J., Campisi, J. J. Biol. Chem. (2004) [Pubmed]
  23. Putative telomere-recruiting domain in the catalytic subunit of human telomerase. Armbruster, B.N., Etheridge, K.T., Broccoli, D., Counter, C.M. Mol. Cell. Biol. (2003) [Pubmed]
  24. The G-quadruplex ligand telomestatin inhibits POT1 binding to telomeric sequences in vitro and induces GFP-POT1 dissociation from telomeres in human cells. Gomez, D., O'Donohue, M.F., Wenner, T., Douarre, C., Macadré, J., Koebel, P., Giraud-Panis, M.J., Kaplan, H., Kolkes, A., Shin-ya, K., Riou, J.F. Cancer Res. (2006) [Pubmed]
  25. Zinc finger protein overexpressed in colon carcinoma interacts with the telomeric protein hRap1. Antoine, K., Ferbus, D., Kolahgar, G., Prospéri, M.T., Goubin, G. J. Cell. Biochem. (2005) [Pubmed]
  26. Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases. Opresko, P.L., von Kobbe, C., Laine, J.P., Harrigan, J., Hickson, I.D., Bohr, V.A. J. Biol. Chem. (2002) [Pubmed]
  27. Association and regulation of the BLM helicase by the telomere proteins TRF1 and TRF2. Lillard-Wetherell, K., Machwe, A., Langland, G.T., Combs, K.A., Behbehani, G.K., Schonberg, S.A., German, J., Turchi, J.J., Orren, D.K., Groden, J. Hum. Mol. Genet. (2004) [Pubmed]
  28. Werner protein protects nonproliferating cells from oxidative DNA damage. Szekely, A.M., Bleichert, F., Nümann, A., Van Komen, S., Manasanch, E., Ben Nasr, A., Canaan, A., Weissman, S.M. Mol. Cell. Biol. (2005) [Pubmed]
  29. Telomerase abrogation dramatically accelerates TRF2-induced epithelial carcinogenesis. Blanco, R., Muñoz, P., Flores, J.M., Klatt, P., Blasco, M.A. Genes Dev. (2007) [Pubmed]
  30. TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts. Brunori, M., Mathieu, N., Ricoul, M., Bauwens, S., Koering, C.E., Roborel de Climens, A., Belleville, A., Wang, Q., Puisieux, I., Décimo, D., Puisieux, A., Sabatier, L., Gilson, E. Oncogene (2006) [Pubmed]
  31. XPF with mutations in its conserved nuclease domain is defective in DNA repair but functions in TRF2-mediated telomere shortening. Wu, Y., Zacal, N.J., Rainbow, A.J., Zhu, X.D. DNA Repair (Amst.) (2007) [Pubmed]
  32. Identification of human Rap1: implications for telomere evolution. Li, B., Oestreich, S., de Lange, T. Cell (2000) [Pubmed]
  33. Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Zhu, X.D., Küster, B., Mann, M., Petrini, J.H., de Lange, T. Nat. Genet. (2000) [Pubmed]
  34. Telomere length homeostasis requires that telomerase levels are limiting. Cristofari, G., Lingner, J. EMBO J. (2006) [Pubmed]
  35. Up-regulation of telomere-binding proteins, TRF1, TRF2, and TIN2 is related to telomere shortening during human multistep hepatocarcinogenesis. Oh, B.K., Kim, Y.J., Park, C., Park, Y.N. Am. J. Pathol. (2005) [Pubmed]
  36. TRF2 functions as a protein hub and regulates telomere maintenance by recognizing specific peptide motifs. Kim, H., Lee, O.H., Xin, H., Chen, L.Y., Qin, J., Chae, H.K., Lin, S.Y., Safari, A., Liu, D., Songyang, Z. Nat. Struct. Mol. Biol. (2009) [Pubmed]
  37. Mammalian telomeres end in a large duplex loop. Griffith, J.D., Comeau, L., Rosenfield, S., Stansel, R.M., Bianchi, A., Moss, H., de Lange, T. Cell (1999) [Pubmed]
  38. Hepatocytes with extensive telomere deprotection and fusion remain viable and regenerate liver mass through endoreduplication. Lazzerini Denchi, E., Celli, G., de Lange, T. Genes Dev. (2006) [Pubmed]
  39. The Bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis. Stavropoulos, D.J., Bradshaw, P.S., Li, X., Pasic, I., Truong, K., Ikura, M., Ungrin, M., Meyn, M.S. Hum. Mol. Genet. (2002) [Pubmed]
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