Replicative Senescence as an Intrinsic Tumor-Suppressor Mechanism

Chapter
First Online:

Abstract

One feature of human carcinomas is their strikingly complex cytogenetic profiles. An important mechanism that can give rise to this level of genomic instability is the functional status of telomeres, the protein-DNA complexes that cap the ends of chromosomes. Telomeres serve to protect eukaryotic chromosomal ends from being recognized as damaged DNA, and growing evidence suggests that critically shortened (dysfunctional) telomeres may help initiate the onset of cancer. Dysfunctional telomeres potently engage the DNA damage response pathway, leading to the onset of cellular senescence when p53 is functional. However, in the absence of p53, dysfunctional telomeres can initiate cancer by promoting genomic instability. In this chapter, I will use mouse models to illustrate the interplay between telomere dysfunction and the development of carcinomas in the setting of an intact or mutated p53-dependent DDR pathway. Dysfunctional telomeres trigger senescence when p53 is functional, thereby protecting epithelial tissues from cancer progression. These results suggest that p53-dependent senescence, induced by dysfunctional telomeres, may be as potent as apoptosis in suppressing tumorigenesis in vivo.

Keywords

Telomere Length Cellular Senescence Replicative Senescence Dicentric Chromosome Telomere Dysfunction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

ALT

Alternative lengthening of telomeres

ATM

Ataxia-telangiectasia mutated

ATR

Ataxia-telangiectasia and Rad3 related

BFB

Breakage-fusion-bridge

DDR

DNA damage response

DSBs

DNA double stranded breaks

HDFs

Human diploid fibroblasts

HR

Homologous recombination

LOH

Loss of heterozygosity

MDM2

Murine double minute 2

NHEJ

Nonhomologous end joining

NRTs

Nonreciprocal translocations

OB

Fold-oligosaccharide/oligonucleotide-binding fold

POT1

Protection of telomeres 1

SA-β-gal

Senescence-associated β-galactosidase

Terc

Telomerase RNA template

Tert

Telomerase reverse transcriptase

TIN2

TRF1 interacting protein 2

TRF1

Telomeric-repeat binding factor 1

TRF2

Telomeric-repeat binding factor 2

This is a preview of subscription content, log in to check access.

References

  1. Adeyinka A, Mertens F, Idvall I, et al. Different patterns of chromosomal imbalances in metastasising and non-metastasising primary breast carcinomas. Int J Cancer. 1999;84:370–375.CrossRefPubMedGoogle Scholar
  2. Allsopp RC, Vaziri H, Patterson C, et al. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA. 1992;89:10114–10118.CrossRefPubMedGoogle Scholar
  3. Artandi SE, Chang S, Lee SL, et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature. 2000;406:641–645.CrossRefPubMedGoogle Scholar
  4. Bae N, Baumann P. A RAP1/TRF2 complex inhibits nonhomologous end-joining at human telomeric DNA ends. Mol Cell. 2007;26:323–334.CrossRefPubMedGoogle Scholar
  5. Bartkova J, Horejsi Z, Koed K, et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature. 2005;434:864–870.CrossRefPubMedGoogle Scholar
  6. Bartkova J, Rezaei N, Liontos M, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444:633–637.CrossRefPubMedGoogle Scholar
  7. Baumann P, Cech TR. Pot1, the putative telomere end-binding protein in fission yeast and humans. Science. 2001;292:1171–1175.CrossRefPubMedGoogle Scholar
  8. Blasco MA, Lee HW, Hande MP, et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell. 1997;91:25–34.CrossRefPubMedGoogle Scholar
  9. Bodnar AG, Ouellette M, Frolkis M, et al. Extension of life-span by introduction of telomerase into normal human cells [see comments]. Science. 1998;279:349–352.CrossRefPubMedGoogle Scholar
  10. Bryan TM, Englezou A, Dalla-Pozza L, et al. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat Med. 1997;3:1271–1274.CrossRefPubMedGoogle Scholar
  11. Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8:729–740.CrossRefPubMedGoogle Scholar
  12. Celli G, de Lange T. DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion. Nat Cell Biol. 2005;7:712–718.CrossRefPubMedGoogle Scholar
  13. Chang S, Khoo C, DePinho RA. Modeling Chromosomal instability and epithelial carcinogenesis in the telomerase deficient mouse. Semin Oncol. 2001;11:227–238.Google Scholar
  14. Chang S, Khoo C, Naylor M, et al. Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression. Genes Dev. 2003;17:88–100.CrossRefPubMedGoogle Scholar
  15. Chang S, Multani AS, Cabrera NG, et al. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nat Genet. 2004;36:877–882.CrossRefPubMedGoogle Scholar
  16. Chin L, Artandi SE, Shen Q, et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell. 1999;97:527–538.CrossRefPubMedGoogle Scholar
  17. Choudhury AR, Ju Z, Djojosubroto MW, et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet. 2007;39:99–105.CrossRefPubMedGoogle Scholar
  18. Churikov D, Price CM Pot1 and cell cycle progression cooperate in telomere length regulation. Nat Struct Mol Biol. 2008;79–84.CrossRefPubMedGoogle Scholar
  19. Cosme-Blanco W, Shen W, Lazar A, et al. Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by activating p53-mediated cellular senescence. EMBO Rep. 2007;8:497–503.CrossRefPubMedGoogle Scholar
  20. Counter CM, Avilion AA, LeFeuvre CE, et al. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 1992;11:1921–1929.PubMedGoogle Scholar
  21. d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426:194–198.CrossRefPubMedGoogle Scholar
  22. de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005;19:2100–2110.CrossRefPubMedGoogle Scholar
  23. Denchi EL, de Lange T. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature. 2007;448:1068–10671.CrossRefPubMedGoogle Scholar
  24. Di Micco R, Fumagalli M, Cicalese A, et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006;444:638–642.CrossRefPubMedGoogle Scholar
  25. Dove WF, Cormier RT, Gould KA, et al. The intestinal epithelium and its neoplasms: genetic, cellular and tissue interactions. Philos Trans R Soc Lond B Biol Sci. 1998;353(1370):915–923.CrossRefPubMedGoogle Scholar
  26. Farazi PA, Glickman J, Jiang S, et al. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma. Cancer Res. 2003;63:5021–5027.PubMedGoogle Scholar
  27. Feldser DM, Greider CW. Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell. 2007;11:461–469.CrossRefPubMedGoogle Scholar
  28. García-Cao I, García-Cao M, Tomás-Loba A, et al. Increased p53 activity does not accelerate telomere-driven ageing. EMBO Rep. 2006;7:546–552.PubMedGoogle Scholar
  29. Gire V, Jobling WA, Cgen DJ, et al. DNA damage checkpoint kinase Chk2 triggers replicative senescence. EMBO J. 2004;23:2554–2563.CrossRefPubMedGoogle Scholar
  30. Gonzalez-Suarez E, Samper E, Flores JM, et al. Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nat Genet. 2000;26:114–117.CrossRefPubMedGoogle Scholar
  31. Gorgoulis V, Vassiliou L, Karakaidos P, et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature. 2005;434:907–913.CrossRefPubMedGoogle Scholar
  32. Greenberg RA, Allsopp RC, Chin L, et al. Expression of mouse telomerase reverse transcriptase during development, differentiation and proliferation. Oncogene. 1998;16:1723–1730.CrossRefPubMedGoogle Scholar
  33. Greenberg RA, Chin L, Femino A, et al. Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse. Cell. 1999;97:515–525.CrossRefPubMedGoogle Scholar
  34. Greenblatt MS, Bennett WP, Hollstein M, et al. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994;54:4855–4878.PubMedGoogle Scholar
  35. Guo X, Deng Y, Lin Y, et al. Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis. EMBO J. 2007;26:4709–4719.CrossRefPubMedGoogle Scholar
  36. Hackett JA, Feldser DM, Greider CW. Telomere dysfunction increases mutation rate and genomic instability. Cell. 2001;106(3):275–286.CrossRefPubMedGoogle Scholar
  37. Hara E, Tsurui H, Shinozaki A, et al. Cooperative effect of antisense-Rb and antisense-p53 oligomers on the extension of life span in human diploid fibroblasts, TIG-1. Biochem Biophys Res Commun. 1991;179:528–534.CrossRefPubMedGoogle Scholar
  38. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345:458–460.CrossRefPubMedGoogle Scholar
  39. Harley CB, Kim NW, Prowse KR, et al. Telomerase, cell immortality, and cancer. Cold Spring Harb Symp Quant Biol. 1994;59:307–315.PubMedGoogle Scholar
  40. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621.CrossRefGoogle Scholar
  41. He H, Multani AS, Cosme-Blanco W, et al. POT1b protects telomeres from end-to-end chromosomal fusions and aberrant homologous recombination. EMBO J. 2006;25:5180–5190.CrossRefPubMedGoogle Scholar
  42. He H, Wang Y, Guo X, et al. Pot1b deletion and telomerase haploinsufficiency in mice initiate an ATR-dependent DNA damage response and elicit phenotypes resembling dyskeratosis congenita. Mol Cell Biol. 2009;29:229–240.CrossRefPubMedGoogle Scholar
  43. Hemann MT, Strong MA, Hao LY, et al. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell. 2001;107:67–77.CrossRefPubMedGoogle Scholar
  44. Herbig U, Jobling WA, Chen BP, et al. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell. 2004;14:501–513.CrossRefPubMedGoogle Scholar
  45. Herrera E, Martinez-A C, Blasco MA. Impaired germinal center reaction in mice with short telomeres. EMBO J. 2000;19:472–481.CrossRefPubMedGoogle Scholar
  46. Hockemeyer D, Daniels JP, Takai H, et al. Recent expansion of the telomeric complex in rodents: Two distinct POT1 proteins protect mouse telomeres. Cell. 2006;126:63–77.CrossRefPubMedGoogle Scholar
  47. Hollstein M, Sidransky D, Vogelstein B, et al. p53 mutations in human cancers. Science. 1991;253:49–53.CrossRefPubMedGoogle Scholar
  48. Jackson SR, Zhu CH, Paulson V et al (2007) Antiadhesive effects of GRN163L – an oligonucleotide N3′- > P5′ thio-phosphoramidate targeting telomerase.Cancer Res 67, 1121–1129Google Scholar
  49. Kamijo T, Zindy F, Roussel MF, et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell. 1997;91:649–659.CrossRefPubMedGoogle Scholar
  50. Karlseder J, Broccoli D, Dai Y, et al. p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science. 1999;283:1321–1325.CrossRefPubMedGoogle Scholar
  51. Kelleher C, Kurth I, Lingner J. Human protection of telomeres 1 (POT1) is a negative regulator of telomerase activity in vitro. Mol Cell Biol. 2005;25:808–818.CrossRefPubMedGoogle Scholar
  52. Kim NW, Piatyszek MA, Prowse KR, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266:2011–2015.CrossRefPubMedGoogle Scholar
  53. Kipling D, Cooke HJ. Hypervariable ultra-long telomeres in mice. Nature. 1990;347:400–402.CrossRefPubMedGoogle Scholar
  54. Lee HW, Blasco MA, Gottlieb GJ, et al. Essential role of mouse telomerase in highly proliferative organs. Nature. 1998;392:569–574.CrossRefPubMedGoogle Scholar
  55. Lei M, Podell ER, Cech TR. Structure of human POT1 bound to telomeric single-stranded DNA provides a model for chromosome end-protection. Nat Struct Mol Biol. 2004;12:1223–1229.CrossRefGoogle Scholar
  56. Lei M, Zaug AJ, Podell ER, et al. Switching human telomerase on and off with hPOT1 protein in vitro. J Biol Chem. 2005;280:20449–20456.CrossRefPubMedGoogle Scholar
  57. Liu G, Parant JM, Lang G, et al. Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat Genet. 2004;36:63–68.CrossRefPubMedGoogle Scholar
  58. Loayza D, De Lange T. POT1 as a terminal transducer of TRF1 telomere length control. Nature. 2003;423:1013–1018.CrossRefPubMedGoogle Scholar
  59. Lundblad V, Blackburn EH. An alternative pathway for yeast telomere maintenance rescues est1-senescence. Cell. 1993;73:347–360.CrossRefPubMedGoogle Scholar
  60. Martin-Rivera L, Herrera E, Albar JP, et al. Expression of mouse telomerase catalytic subunit in embryos and adult tissues. Proc Natl Acad Sci USA. 1998;95:10471–10476.CrossRefPubMedGoogle Scholar
  61. Maser RS, DePinho RA. Connecting chromosomes, crisis, and cancer. Science. 2002;297:565–569.CrossRefPubMedGoogle Scholar
  62. McClintock B. The stability of broken ends of chromosomes in Zea mays. Genetics. 1941;26:143–179.Google Scholar
  63. Mendrysa SM, O’Leary KA, McElwee MK, Michalowski J, Eisenman RN, Powell DA, et al. Tumor suppression and normal aging in mice with constitutively high p53 activity. Genes Dev. 2006;20:16–21.CrossRefPubMedGoogle Scholar
  64. Meyerson M, Counter CM, Eaton EN, et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell. 1997;90:785–795.CrossRefPubMedGoogle Scholar
  65. Nakamura TM, Morin GB, Chapman KB, et al. Telomerase catalytic subunit homologs from fission yeast and human. Science. 1997;277:955–959.CrossRefPubMedGoogle Scholar
  66. Newbold RF. Genetic control of telomerase and replicative senescence in human and rodent cells. Ciba Found Symp. 1997;211:177–189.PubMedGoogle Scholar
  67. O’Hagan RC, Chang S, Maser RS, et al. Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell. 2002;2:149–155.CrossRefPubMedGoogle Scholar
  68. Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet. 2008;42:301–334.CrossRefPubMedGoogle Scholar
  69. Prowse KR, Greider CW. Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc Natl Acad Sci USA. 1995;92:4818–4822.CrossRefPubMedGoogle Scholar
  70. Prowse KR, Avilion AA, Greider CW. Identification of a nonprocessive telomerase activity from mouse cells. Proc Natl Acad Sci USA. 1993;90:1493–1497.CrossRefPubMedGoogle Scholar
  71. Rudolph KL, Chang S, Lee HW, et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell. 1999;96:701–712.CrossRefPubMedGoogle Scholar
  72. Rudolph KL, Millard M, Bosenberg MW, et al. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet. 2001;28:155–159.CrossRefPubMedGoogle Scholar
  73. Samper E, Flores JM, Blasco MA. Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc−/− mice with short telomeres. EMBO Rep. 2001;2:800–807.CrossRefPubMedGoogle Scholar
  74. Serrano M, Lee H, Chin L, et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell. 1996;85:27–37.CrossRefPubMedGoogle Scholar
  75. Shay JW, Bacchetti S. A survey of telomerase activity in human cancer. Eur J Cancer. 1997;33:787–791.CrossRefPubMedGoogle Scholar
  76. Shay JW, Pereira-Smith OM, Wright WE. A role for both RB and p53 in the regulation of human cellular senescence. Exp Cell Res. 1991;196:33–39.CrossRefPubMedGoogle Scholar
  77. Shay JW, Van Der Haegen BA, Ying Y, et al. The frequency of immortalization of human fibroblasts and mammary epithelial cells transfected with SV40 large T-antigen. Exp Cell Res. 1993;209:45–52.CrossRefPubMedGoogle Scholar
  78. Smogorzewska A, de Lange T. Different telomere damage signaling pathways in human and mouse cells. EMBO J. 2002;21:4338–4438.CrossRefPubMedGoogle Scholar
  79. Takai H, Smogorzewska A, de Lange T. DNA damage foci at dysfunctional telomeres. Curr Biol. 2003;13:1549–1556.CrossRefPubMedGoogle Scholar
  80. Van Steensel B, Smogorzewska A, de Lange T. TRF2 protects human telomeres from end-to-end fusions. Cell. 1998;92:401–413.CrossRefPubMedGoogle Scholar
  81. Vaziri H, Benchimol S. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr Biol. 1998;8:279–282.CrossRefPubMedGoogle Scholar
  82. Veldman T, Etheridge KT, Counter CM. Loss of hPot1 function leads to telomere instability and a cut-like phenotype. Curr Biol. 2004;14:2264–2270.CrossRefPubMedGoogle Scholar
  83. Veloso M, Wrba F, Kaserer K, et al. p53 gene status and expression of p53, mdm2, and p21Waf1/Cip1 proteins in colorectal cancer. Virchows Arch. 2000;437:241–247.CrossRefPubMedGoogle Scholar
  84. Ventura A, Kirsch DG, McLaughlin ME, et al. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007;445:661–665.CrossRefPubMedGoogle Scholar
  85. Verdun RE, Karlseder J. Replication and protection of telomeres. Nature. 2007;447:924–931.CrossRefPubMedGoogle Scholar
  86. Weng NP, Granger L, Hodes RJ. Telomere lengthening and telomerase activation during human B cell differentiation. Proc Natl Acad Sci USA. 1997;94:10827–10832.CrossRefPubMedGoogle Scholar
  87. Wright WE, Shay JW. The two-stage mechanism controlling cellular senescence and immortalization. Exp Gerontol. 1992;27:383–389.CrossRefPubMedGoogle Scholar
  88. Wright WE, Piatyszek MA, Rainey WE, et al. Telomerase activity in human germline and embryonic tissues and cells. Dev Genet. 1996;18:173–179.CrossRefPubMedGoogle Scholar
  89. Wu L, Multani AS, He H, et al. Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres. Cell. 2006;126:49–62.CrossRefPubMedGoogle Scholar
  90. Yang Q, Zheng YL, Harris CC. POT1 and TRF2 cooperate to maintain telomeric integrity. Mol Cell Biol. 2005;25:1070–1080.CrossRefPubMedGoogle Scholar
  91. Zijlmans JM, Martens UM, Poon SS, et al. Telomeres in the mouse have large inter-chromosomal variations in the number of T2AG3 repeats. Proc Natl Acad Sci USA. 1997;94:7423–7428.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Genetics, Unit 1006U.T.M.D. Anderson Cancer CenterHoustonUSA

Personalised recommendations