Development - Regulation of telomere length and cellular immortalization

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Regulation of telomere length and cellular immortalization

Telomeres are the physical ends of the chromosomes. They are composed of the repeated sequence TTAGGG and multiple protein components and are responsible for maintaining chromosomal stability and prevent chromosomal end-joining [1], [2], [3]. In chromosomes telomeres serve as stabilizing caps [2]. During the proliferation of mammalian cells, the telomere shortens after every round of DNA replication [4]. Telomerase, a specialized RNA-directed DNA polymerase that extends telomeres of eukaryotic chromosomes, is repressed in normal human somatic cells but is activated during development and upon neoplasia [1], [5], [6], [7], [8]. Because the lost sequences of the telomeres at each replication cycle can be resynthesized by telomerase, the enzyme has essential functions for cellular immortalization [1], [9].

The human telomerase complex is a ribonucleoprotein containing an integral RNA: Telomerase RNA component (TERC), a Telomerase reverse transcriptase (TERT), and several associated proteins [10].

Telomerase-associated protein 1 (TEP1), Heat shock protein 90kDa (HSP90), Prostaglandin E synthase 3 (p23 co-chaperone), DKC1 dyskeratosis congenita 1, dyskerin (Dyskerin) (NAP57)), Staufen, RNA binding protein, homolog 1 (Staufen), Heterogeneous nuclear ribonucleoprotein C (hnRNPC), Ribosomal protein L22 (RPL22), X-ray repair complementing defective repair in Chinese hamster cells 6/ 5 (Ku70/80) interact with TERC and TERT and are associated with telomerase activity [6], [11], [12], [13], [14], [15], [16]. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) associates with Telomeric DNA and hnRNP C and stimulates telomerase activity [17], [18].

Telomerase activity can be regulated by transcriptional and post-translational mechanisms. v-myc myelocytomatosis viral oncogene homolog (c-Myc), MYC associated factor X (Max), Sp1 transcription factor (SP1) and E2F transcription factor 1 (E2F1) activate transcription of TERT [19], [6], [20], [21]. Protein kinase C, alpha (PKC-alpha) stimulates telomerase activity by phosphorylation of TERT-associated TEP1 and by direct phosphorylation of TERT [22], [23]. Activation of Phosphoinositide-3-kinase, catalytic (PI3K cat class IA)/ v-akt murine thymoma viral oncogene homologs (AKT(PKB)) pathway leads to AKT(PKB) association with HSP90 and subsequent phosphorylation of TERT promoting activation of telomerase and telomere elongation [3], [23], [24].

Telomere binding proteins affects telomere maintenance by modulating the activity of telomerase [2], [9]. Telomeric repeat binding factors 1 and 2 (TRF1 and TRF2) associate with Telomeric DNA and have an essential role in regulation of telomerase activity and protection and maintenance of telomere ends [4], [25], [26], [27], [28], [29]. TRF1 can control telomerase access through its interaction with TERF1 (TRF1)-interacting nuclear factor 2 (TIN2), Adrenocortical dysplasia homolog (PTOP), Protection of telomeres 1 homolog (POT1), Ku80, Tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase (Tankyrase 2) and PIN2/TERF1 interacting, telomerase inhibitor 1 (PINX1) [2], [14], [15], [26], [29]. TIN2 suppresses Tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase (Tankyrase 1) - mediated poly(ADP-ribos)ylation of TRF1 thereby activating TRF1 [30], [31], [32], [33], [34]. The latter promotes PINX1 localization in telomeres, and PINX1 enhances TRF1 interaction with Telomeric DNA [35]. PINX1 binds both TERT and TERC and inhibits telomerase activity thereby promoting maintenance of telomere length [15], [36], [37], [38].

TRF2 in association with Telomeric repeat binding factor 2, interacting protein (hRap1), MRN complex, POT1 and PTOP inhibits telomerase activity leading to telomere length stabilization thereby promoting cellular immortalization [2], [4], [15], [26], [28], [29], [39], [40], [41], [42].

References:

  1. Dahse R, Fiedler W, Ernst G
    Telomeres and telomerase: biological and clinical importance. Clinical chemistry 1997 May;43(5):708-14
  2. Saldanha SN, Andrews LG, Tollefsbol TO
    Assessment of telomere length and factors that contribute to its stability. European journal of biochemistry / FEBS 2003 Feb;270(3):389-403
  3. Haendeler J, Hoffmann J, Rahman S, Zeiher AM, Dimmeler S
    Regulation of telomerase activity and anti-apoptotic function by protein-protein interaction and phosphorylation. FEBS letters 2003 Feb 11;536(1-3):180-6
  4. Okabe J, Eguchi A, Masago A, Hayakawa T, Nakanishi M
    TRF1 is a critical trans-acting factor required for de novo telomere formation in human cells. Human molecular genetics 2000 Nov 1;9(18):2639-50
  5. Kipling D
    Telomerase: immortality enzyme or oncogene? Nature genetics 1995 Feb;9(2):104-6
  6. Liu JP
    Studies of the molecular mechanisms in the regulation of telomerase activity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1999 Dec;13(15):2091-104
  7. Shay JW, Zou Y, Hiyama E, Wright WE
    Telomerase and cancer. Human molecular genetics 2001 Apr;10(7):677-85
  8. Chang S, DePinho RA
    Telomerase extracurricular activities. Proceedings of the National Academy of Sciences of the United States of America 2002 Oct 1;99(20):12520-2
  9. Colgin LM, Reddel RR
    Telomere maintenance mechanisms and cellular immortalization. Current opinion in genetics & development 1999 Feb;9(1):97-103
  10. Cohen SB, Graham ME, Lovrecz GO, Bache N, Robinson PJ, Reddel RR
    Protein composition of catalytically active human telomerase from immortal cells. Science (New York, N.Y.) 2007 Mar 30;315(5820):1850-3
  11. Harrington L, McPhail T, Mar V, Zhou W, Oulton R, Bass MB, Arruda I, Robinson MO
    A mammalian telomerase-associated protein. Science (New York, N.Y.) 1997 Feb 14;275(5302):973-7
  12. Le S, Sternglanz R, Greider CW
    Identification of two RNA-binding proteins associated with human telomerase RNA. Molecular biology of the cell 2000 Mar;11(3):999-1010
  13. Ford LP, Suh JM, Wright WE, Shay JW
    Heterogeneous nuclear ribonucleoproteins C1 and C2 associate with the RNA component of human telomerase. Molecular and cellular biology 2000 Dec;20(23):9084-91
  14. Ford LP, Wright WE, Shay JW
    A model for heterogeneous nuclear ribonucleoproteins in telomere and telomerase regulation. Oncogene 2002 Jan 21;21(4):580-3
  15. Chai W, Ford LP, Lenertz L, Wright WE, Shay JW
    Human Ku70/80 associates physically with telomerase through interaction with hTERT. The Journal of biological chemistry 2002 Dec 6;277(49):47242-7
  16. Ting NS, Yu Y, Pohorelic B, Lees-Miller SP, Beattie TL
    Human Ku70/80 interacts directly with hTR, the RNA component of human telomerase. Nucleic acids research 2005;33(7):2090-8
  17. LaBranche H, Dupuis S, Ben-David Y, Bani MR, Wellinger RJ, Chabot B
    Telomere elongation by hnRNP A1 and a derivative that interacts with telomeric repeats and telomerase. Nature genetics 1998 Jun;19(2):199-202
  18. Zhang QS, Manche L, Xu RM, Krainer AR
    hnRNP A1 associates with telomere ends and stimulates telomerase activity. RNA (New York, N.Y.) 2006 Jun;12(6):1116-28
  19. Wu KJ, Grandori C, Amacker M, Simon-Vermot N, Polack A, Lingner J, Dalla-Favera R
    Direct activation of TERT transcription by c-MYC. Nature genetics 1999 Feb;21(2):220-4
  20. Kyo S, Takakura M, Taira T, Kanaya T, Itoh H, Yutsudo M, Ariga H, Inoue M
    Sp1 cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene (hTERT). Nucleic acids research 2000 Feb 1;28(3):669-77
  21. Wang J, Hannon GJ, Beach DH
    Risky immortalization by telomerase. Nature 2000 Jun 15;405(6788):755-6
  22. Li H, Zhao L, Yang Z, Funder JW, Liu JP
    Telomerase is controlled by protein kinase Calpha in human breast cancer cells. The Journal of biological chemistry 1998 Dec 11;273(50):33436-42
  23. Kang SS, Kwon T, Kwon DY, Do SI
    Akt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit. The Journal of biological chemistry 1999 May 7;274(19):13085-90
  24. Breitschopf K, Zeiher AM, Dimmeler S
    Pro-atherogenic factors induce telomerase inactivation in endothelial cells through an Akt-dependent mechanism. FEBS letters 2001 Mar 23;493(1):21-5
  25. Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G, de Lange T
    Control of human telomere length by TRF1 and TRF2. Molecular and cellular biology 2000 Mar;20(5):1659-68
  26. Karlseder J
    Telomere repeat binding factors: keeping the ends in check. Cancer letters 2003 May 15;194(2):189-97
  27. Nishikawa T, Okamura H, Nagadoi A, Koig P, Rhodes D, Nishimura Y
    Structure of the DNA-binding domain of human telomeric protein, TRF1 and its interaction with telomeric DNA. Nucleic acids research. Supplement (2001) 2001;(1):273-4
  28. Liu D, O'Connor MS, Qin J, Songyang Z
    Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. The Journal of biological chemistry 2004 Dec 3;279(49):51338-42
  29. De Boeck G, Forsyth RG, Praet M, Hogendoorn PC
    Telomere-associated proteins: cross-talk between telomere maintenance and telomere-lengthening mechanisms. The Journal of pathology 2009 Feb;217(3):327-44
  30. Smith S, de Lange T
    Tankyrase promotes telomere elongation in human cells. Current biology : CB 2000 Oct 19;10(20):1299-302
  31. Cook BD, Dynek JN, Chang W, Shostak G, Smith S
    Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Molecular and cellular biology 2002 Jan;22(1):332-42
  32. Chang W, Dynek JN, Smith S
    TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres. Genes & development 2003 Jun 1;17(11):1328-33
  33. Ye JZ, de Lange T
    TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nature genetics 2004 Jun;36(6):618-23
  34. Houghtaling BR, Cuttonaro L, Chang W, Smith S
    A dynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2. Current biology : CB 2004 Sep 21;14(18):1621-31
  35. Yoo JE, Oh BK, Park YN
    Human PinX1 mediates TRF1 accumulation in nucleolus and enhances TRF1 binding to telomeres. Journal of molecular biology 2009 May 22;388(5):928-40
  36. Zhou XZ, Lu KP
    The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor. Cell 2001 Nov 2;107(3):347-59
  37. Banik SS, Counter CM
    Characterization of interactions between PinX1 and human telomerase subunits hTERT and hTR. The Journal of biological chemistry 2004 Dec 10;279(50):51745-8
  38. Chen G, Da L, Xu Y, Xu M, Song L, Li T, Zhao M
    C-terminal amino acids 290-328 of LPTS/PinX1 confer telomerase inhibition. Biochemical and biophysical research communications 2010 Aug 6;398(4):683-9
  39. Zhu XD, Küster B, Mann M, Petrini JH, de Lange T
    Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nature genetics 2000 Jul;25(3):347-52
  40. O'Connor MS, Safari A, Liu D, Qin J, Songyang Z
    The human Rap1 protein complex and modulation of telomere length. The Journal of biological chemistry 2004 Jul 2;279(27):28585-91
  41. Bae NS, Baumann P
    A RAP1/TRF2 complex inhibits nonhomologous end-joining at human telomeric DNA ends. Molecular cell 2007 May 11;26(3):323-34
  42. Attwooll CL, Akpinar M, Petrini JH
    The mre11 complex and the response to dysfunctional telomeres. Molecular and cellular biology 2009 Oct;29(20):5540-51

  1. Dahse R, Fiedler W, Ernst G
    Telomeres and telomerase: biological and clinical importance. Clinical chemistry 1997 May;43(5):708-14
  2. Saldanha SN, Andrews LG, Tollefsbol TO
    Assessment of telomere length and factors that contribute to its stability. European journal of biochemistry / FEBS 2003 Feb;270(3):389-403
  3. Haendeler J, Hoffmann J, Rahman S, Zeiher AM, Dimmeler S
    Regulation of telomerase activity and anti-apoptotic function by protein-protein interaction and phosphorylation. FEBS letters 2003 Feb 11;536(1-3):180-6
  4. Okabe J, Eguchi A, Masago A, Hayakawa T, Nakanishi M
    TRF1 is a critical trans-acting factor required for de novo telomere formation in human cells. Human molecular genetics 2000 Nov 1;9(18):2639-50
  5. Kipling D
    Telomerase: immortality enzyme or oncogene? Nature genetics 1995 Feb;9(2):104-6
  6. Liu JP
    Studies of the molecular mechanisms in the regulation of telomerase activity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1999 Dec;13(15):2091-104
  7. Shay JW, Zou Y, Hiyama E, Wright WE
    Telomerase and cancer. Human molecular genetics 2001 Apr;10(7):677-85
  8. Chang S, DePinho RA
    Telomerase extracurricular activities. Proceedings of the National Academy of Sciences of the United States of America 2002 Oct 1;99(20):12520-2
  9. Colgin LM, Reddel RR
    Telomere maintenance mechanisms and cellular immortalization. Current opinion in genetics & development 1999 Feb;9(1):97-103
  10. Cohen SB, Graham ME, Lovrecz GO, Bache N, Robinson PJ, Reddel RR
    Protein composition of catalytically active human telomerase from immortal cells. Science (New York, N.Y.) 2007 Mar 30;315(5820):1850-3
  11. Harrington L, McPhail T, Mar V, Zhou W, Oulton R, Bass MB, Arruda I, Robinson MO
    A mammalian telomerase-associated protein. Science (New York, N.Y.) 1997 Feb 14;275(5302):973-7
  12. Le S, Sternglanz R, Greider CW
    Identification of two RNA-binding proteins associated with human telomerase RNA. Molecular biology of the cell 2000 Mar;11(3):999-1010
  13. Ford LP, Suh JM, Wright WE, Shay JW
    Heterogeneous nuclear ribonucleoproteins C1 and C2 associate with the RNA component of human telomerase. Molecular and cellular biology 2000 Dec;20(23):9084-91
  14. Ford LP, Wright WE, Shay JW
    A model for heterogeneous nuclear ribonucleoproteins in telomere and telomerase regulation. Oncogene 2002 Jan 21;21(4):580-3
  15. Chai W, Ford LP, Lenertz L, Wright WE, Shay JW
    Human Ku70/80 associates physically with telomerase through interaction with hTERT. The Journal of biological chemistry 2002 Dec 6;277(49):47242-7
  16. Ting NS, Yu Y, Pohorelic B, Lees-Miller SP, Beattie TL
    Human Ku70/80 interacts directly with hTR, the RNA component of human telomerase. Nucleic acids research 2005;33(7):2090-8
  17. LaBranche H, Dupuis S, Ben-David Y, Bani MR, Wellinger RJ, Chabot B
    Telomere elongation by hnRNP A1 and a derivative that interacts with telomeric repeats and telomerase. Nature genetics 1998 Jun;19(2):199-202
  18. Zhang QS, Manche L, Xu RM, Krainer AR
    hnRNP A1 associates with telomere ends and stimulates telomerase activity. RNA (New York, N.Y.) 2006 Jun;12(6):1116-28
  19. Wu KJ, Grandori C, Amacker M, Simon-Vermot N, Polack A, Lingner J, Dalla-Favera R
    Direct activation of TERT transcription by c-MYC. Nature genetics 1999 Feb;21(2):220-4
  20. Kyo S, Takakura M, Taira T, Kanaya T, Itoh H, Yutsudo M, Ariga H, Inoue M
    Sp1 cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene (hTERT). Nucleic acids research 2000 Feb 1;28(3):669-77
  21. Wang J, Hannon GJ, Beach DH
    Risky immortalization by telomerase. Nature 2000 Jun 15;405(6788):755-6
  22. Li H, Zhao L, Yang Z, Funder JW, Liu JP
    Telomerase is controlled by protein kinase Calpha in human breast cancer cells. The Journal of biological chemistry 1998 Dec 11;273(50):33436-42
  23. Kang SS, Kwon T, Kwon DY, Do SI
    Akt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit. The Journal of biological chemistry 1999 May 7;274(19):13085-90
  24. Breitschopf K, Zeiher AM, Dimmeler S
    Pro-atherogenic factors induce telomerase inactivation in endothelial cells through an Akt-dependent mechanism. FEBS letters 2001 Mar 23;493(1):21-5
  25. Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G, de Lange T
    Control of human telomere length by TRF1 and TRF2. Molecular and cellular biology 2000 Mar;20(5):1659-68
  26. Karlseder J
    Telomere repeat binding factors: keeping the ends in check. Cancer letters 2003 May 15;194(2):189-97
  27. Nishikawa T, Okamura H, Nagadoi A, Koig P, Rhodes D, Nishimura Y
    Structure of the DNA-binding domain of human telomeric protein, TRF1 and its interaction with telomeric DNA. Nucleic acids research. Supplement (2001) 2001;(1):273-4
  28. Liu D, O'Connor MS, Qin J, Songyang Z
    Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. The Journal of biological chemistry 2004 Dec 3;279(49):51338-42
  29. De Boeck G, Forsyth RG, Praet M, Hogendoorn PC
    Telomere-associated proteins: cross-talk between telomere maintenance and telomere-lengthening mechanisms. The Journal of pathology 2009 Feb;217(3):327-44
  30. Smith S, de Lange T
    Tankyrase promotes telomere elongation in human cells. Current biology : CB 2000 Oct 19;10(20):1299-302
  31. Cook BD, Dynek JN, Chang W, Shostak G, Smith S
    Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Molecular and cellular biology 2002 Jan;22(1):332-42
  32. Chang W, Dynek JN, Smith S
    TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres. Genes & development 2003 Jun 1;17(11):1328-33
  33. Ye JZ, de Lange T
    TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nature genetics 2004 Jun;36(6):618-23
  34. Houghtaling BR, Cuttonaro L, Chang W, Smith S
    A dynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2. Current biology : CB 2004 Sep 21;14(18):1621-31
  35. Yoo JE, Oh BK, Park YN
    Human PinX1 mediates TRF1 accumulation in nucleolus and enhances TRF1 binding to telomeres. Journal of molecular biology 2009 May 22;388(5):928-40
  36. Zhou XZ, Lu KP
    The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor. Cell 2001 Nov 2;107(3):347-59
  37. Banik SS, Counter CM
    Characterization of interactions between PinX1 and human telomerase subunits hTERT and hTR. The Journal of biological chemistry 2004 Dec 10;279(50):51745-8
  38. Chen G, Da L, Xu Y, Xu M, Song L, Li T, Zhao M
    C-terminal amino acids 290-328 of LPTS/PinX1 confer telomerase inhibition. Biochemical and biophysical research communications 2010 Aug 6;398(4):683-9
  39. Zhu XD, Küster B, Mann M, Petrini JH, de Lange T
    Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nature genetics 2000 Jul;25(3):347-52
  40. O'Connor MS, Safari A, Liu D, Qin J, Songyang Z
    The human Rap1 protein complex and modulation of telomere length. The Journal of biological chemistry 2004 Jul 2;279(27):28585-91
  41. Bae NS, Baumann P
    A RAP1/TRF2 complex inhibits nonhomologous end-joining at human telomeric DNA ends. Molecular cell 2007 May 11;26(3):323-34
  42. Attwooll CL, Akpinar M, Petrini JH
    The mre11 complex and the response to dysfunctional telomeres. Molecular and cellular biology 2009 Oct;29(20):5540-51

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