DNA damage - Inhibition of telomerase activity and cellular senescence

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Inhibition of telomerase activity and cellular senescence

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. Critical telomere shortening or uncapping of telomere binding proteins result in telomere dysfunction initiating DNA damage response signals that contribute to either cellular senescence or apoptosis [4]. Lost sequences of the telomeres at each replication cycle can be resynthesized by telomerase [5]. Telomerase is repressed in normal human somatic cells but is activated during development and upon neoplasia [1], [6], [7], [8]. Repression of telomerase activity contributes to cellular senescence and apoptosis [4], [8], [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 activity can be regulated by transcriptional and post-translational mechanisms. Tumor protein p53 (p53) and Breast cancer 1, early onset (Brca1) inhibit transcription of TERT [11], [12]. In addition, p53 binds and suppresses activity of Telomerase-associated protein 1 (TEP1) leading to inhibition of telomerase complex [7], [13]. p53, Tumor protein p73 (p73) and Cyclin-dependent kinase inhibitor 2A (p16INK4) also bind and inhibit Sp1 transcription factor (SP1) leading to suppression of transcription of TERT [14], [15], [16]. p53 inhibits expression of TERT via induction of transcription of Cyclin-dependent kinase inhibitor 1A (p21) [17]. p21 and p16INK4 bind and inactivate cyclin-dependent kinases 2, 4 and 6 (CDK2, CDK4 and CDK6) leading to activation of Retinoblastoma 1 (Rb protein), Retinoblastoma-like 1 and 2 (p107, p130) that bind and inhibit E2F transcription factor 1 (E2F1) [7], [18]. Inhibition of E2F1 leads to suppression of TERT transcription [14], [18], [19].

Protein phosphatase 2, catalytic subunit (PP2A catalytic) dephosphorylates TEP1, v-akt murine thymoma viral oncogene homologs (AKT(PKB)) and TERT leading to inhibition of telomerase activity [3], [7], [20], [21].

Sjogren syndrome antigen B (La protein) binds and suppresses TERC promoting telomere shortening [22].

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. Ohtani N, Mann DJ, Hara E
    Cellular senescence: its role in tumor suppression and aging. Cancer science 2009 May;100(5):792-7
  5. 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
  6. Kipling D
    Telomerase: immortality enzyme or oncogene? Nature genetics 1995 Feb;9(2):104-6
  7. 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
  8. Shay JW, Zou Y, Hiyama E, Wright WE
    Telomerase and cancer. Human molecular genetics 2001 Apr;10(7):677-85
  9. Fossel M
    Telomerase and the aging cell: implications for human health. JAMA : the journal of the American Medical Association 1998 Jun 3;279(21):1732-5
  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. Stampfer MR, Garbe J, Nijjar T, Wigington D, Swisshelm K, Yaswen P
    Loss of p53 function accelerates acquisition of telomerase activity in indefinite lifespan human mammary epithelial cell lines. Oncogene 2003 Aug 14;22(34):5238-51
  12. 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
  13. Li H, Cao Y, Berndt MC, Funder JW, Liu JP
    Molecular interactions between telomerase and the tumor suppressor protein p53 in vitro. Oncogene 1999 Nov 18;18(48):6785-94
  14. Won J, Yim J, Kim TK
    Opposing regulatory roles of E2F in human telomerase reverse transcriptase (hTERT) gene expression in human tumor and normal somatic cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2002 Dec;16(14):1943-5
  15. Saito M, Nakagawa K, Hamada K, Hirose S, Harada H, Kohno S, Nagato S, Ohnishi T
    Introduction of p16INK4a inhibits telomerase activity through transcriptional suppression of human telomerase reverse transcriptase expression in human gliomas. International journal of oncology 2004 May;24(5):1213-20
  16. Beitzinger M, Oswald C, Beinoraviciute-Kellner R, Stiewe T
    Regulation of telomerase activity by the p53 family member p73. Oncogene 2006 Feb 9;25(6):813-26
  17. Shats I, Milyavsky M, Tang X, Stambolsky P, Erez N, Brosh R, Kogan I, Braunstein I, Tzukerman M, Ginsberg D, Rotter V
    p53-dependent down-regulation of telomerase is mediated by p21waf1. The Journal of biological chemistry 2004 Dec 3;279(49):50976-85
  18. Gizard F, Nomiyama T, Zhao Y, Findeisen HM, Heywood EB, Jones KL, Staels B, Bruemmer D
    The PPARalpha/p16INK4a pathway inhibits vascular smooth muscle cell proliferation by repressing cell cycle-dependent telomerase activation. Circulation research 2008 Nov 7;103(10):1155-63
  19. Xu HJ, Zhou Y, Ji W, Perng GS, Kruzelock R, Kong CT, Bast RC, Mills GB, Li J, Hu SX
    Reexpression of the retinoblastoma protein in tumor cells induces senescence and telomerase inhibition. Oncogene 1997 Nov 20;15(21):2589-96
  20. 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
  21. 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
  22. Ford LP, Shay JW, Wright WE
    The La antigen associates with the human telomerase ribonucleoprotein and influences telomere length in vivo. RNA (New York, N.Y.) 2001 Aug;7(8):1068-75

  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. Ohtani N, Mann DJ, Hara E
    Cellular senescence: its role in tumor suppression and aging. Cancer science 2009 May;100(5):792-7
  5. 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
  6. Kipling D
    Telomerase: immortality enzyme or oncogene? Nature genetics 1995 Feb;9(2):104-6
  7. 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
  8. Shay JW, Zou Y, Hiyama E, Wright WE
    Telomerase and cancer. Human molecular genetics 2001 Apr;10(7):677-85
  9. Fossel M
    Telomerase and the aging cell: implications for human health. JAMA : the journal of the American Medical Association 1998 Jun 3;279(21):1732-5
  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. Stampfer MR, Garbe J, Nijjar T, Wigington D, Swisshelm K, Yaswen P
    Loss of p53 function accelerates acquisition of telomerase activity in indefinite lifespan human mammary epithelial cell lines. Oncogene 2003 Aug 14;22(34):5238-51
  12. 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
  13. Li H, Cao Y, Berndt MC, Funder JW, Liu JP
    Molecular interactions between telomerase and the tumor suppressor protein p53 in vitro. Oncogene 1999 Nov 18;18(48):6785-94
  14. Won J, Yim J, Kim TK
    Opposing regulatory roles of E2F in human telomerase reverse transcriptase (hTERT) gene expression in human tumor and normal somatic cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2002 Dec;16(14):1943-5
  15. Saito M, Nakagawa K, Hamada K, Hirose S, Harada H, Kohno S, Nagato S, Ohnishi T
    Introduction of p16INK4a inhibits telomerase activity through transcriptional suppression of human telomerase reverse transcriptase expression in human gliomas. International journal of oncology 2004 May;24(5):1213-20
  16. Beitzinger M, Oswald C, Beinoraviciute-Kellner R, Stiewe T
    Regulation of telomerase activity by the p53 family member p73. Oncogene 2006 Feb 9;25(6):813-26
  17. Shats I, Milyavsky M, Tang X, Stambolsky P, Erez N, Brosh R, Kogan I, Braunstein I, Tzukerman M, Ginsberg D, Rotter V
    p53-dependent down-regulation of telomerase is mediated by p21waf1. The Journal of biological chemistry 2004 Dec 3;279(49):50976-85
  18. Gizard F, Nomiyama T, Zhao Y, Findeisen HM, Heywood EB, Jones KL, Staels B, Bruemmer D
    The PPARalpha/p16INK4a pathway inhibits vascular smooth muscle cell proliferation by repressing cell cycle-dependent telomerase activation. Circulation research 2008 Nov 7;103(10):1155-63
  19. Xu HJ, Zhou Y, Ji W, Perng GS, Kruzelock R, Kong CT, Bast RC, Mills GB, Li J, Hu SX
    Reexpression of the retinoblastoma protein in tumor cells induces senescence and telomerase inhibition. Oncogene 1997 Nov 20;15(21):2589-96
  20. 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
  21. 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
  22. Ford LP, Shay JW, Wright WE
    The La antigen associates with the human telomerase ribonucleoprotein and influences telomere length in vivo. RNA (New York, N.Y.) 2001 Aug;7(8):1068-75

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