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Annual Review of Cancer Biology

Volume 5, 2021

Telomeres and Cancer: Resolving the Paradox

Abstract

Decades of study on cell cycle regulation have provided great insight into human cellular life span barriers, as well as their dysregulation during tumorigenesis. Telomeres, the extremities of linear chromosomes, perform an essential role in implementing these proliferative boundaries and preventing the propagation of potentially cancerous cells. The tumor-suppressive function of telomeres relies on their ability to initiate DNA damage signaling pathways and downstream cellular events, ranging from cell cycle perturbation to inflammation and cell death. While the tumor-suppressor role of telomeres is undoubtable, recent advances have pointed to telomeres as a major source of many of the genomic aberrations found in both early- and late-stage cancers, including the most recently discovered mutational phenomenon of chromothripsis. Telomere shortening appears as a double-edged sword that can function in opposing directions in carcinogenesis. This review focuses on the current knowledge of the dual role of telomeres in cancer and suggests a new perspective to reconcile the paradox of telomeres and their implications in cancer etiology.

Keyword(s): genome instability, proliferative life span barriers, replicative crisis, replicative senescence, telomere, tumorigenesis
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2021-03-04
2024-05-08
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Literature Cited

  1. Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D, Barrett JC 1996. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal humanfibroblasts. PNAS 93:2413742–47
     [Google Scholar]
  2. Amiard S, Doudeau M, Pinte S, Poulet A, Lenain C et al. 2007. A topological mechanism for TRF2-enhanced strand invasion. Nat. Struct. Mol. Biol. 14:2147–54
     [Google Scholar]
  3. Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ et al. 2000. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406:6796641–45
     [Google Scholar]
  4. Barthel FP, Wei W, Tang M, Martinez-Ledesma E, Hu X et al. 2017. Systematic analysis of telomere length and somatic alterations in 31 cancer types. Nat. Genet. 49:3349–57
     [Google Scholar]
  5. Baumann P, Cech TR. 2001. Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 292:55191171–75
     [Google Scholar]
  6. Ben-Porath I, Weinberg RA. 2005. The signals and pathways activating cellular senescence. Int. J. Biochem. Cell Biol. 37:5961–76
     [Google Scholar]
  7. Bilaud T, Brun C, Ancelin K, Koering CE, Laroche T, Gilson E 1997. Telomeric localization of TRF2, a novel human telobox protein. Nat. Genet. 17:2236–39
     [Google Scholar]
  8. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP et al. 1998. Extension of life-span by introduction of telomerase into normal human cells. Science 279:5349349–52
     [Google Scholar]
  9. Broccoli D, Smogorzewska A, Chong L, de Lange T 1997. Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. Nat. Genet. 17:2231–35
     [Google Scholar]
  10. Bryan TM, Englezou A, Gupta J, Bacchetti S, Reddel RR 1995. Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J 14:174240–48
     [Google Scholar]
  11. Capper R, Britt-Compton B, Tankimanova M, Rowson J, Letsolo B et al. 2007. The nature of telomere fusion and a definition of the critical telomere length in human cells. Genes Dev 21:192495–508
     [Google Scholar]
  12. Cesare AJ, Hayashi MT, Crabbe L, Karlseder J 2013. The telomere deprotection response is functionally distinct from the genomic DNA damage response. Mol. Cell 51:2141–55
     [Google Scholar]
  13. Cesare AJ, Karlseder J. 2012. A three-state model of telomere control over human proliferative boundaries. Curr. Opin. Cell Biol. 24:6731–38
     [Google Scholar]
  14. Chen YA, Shen YL, Hsia HY, Tiang YP, Sung TL, Chen LY 2017. Extrachromosomal telomere repeat DNA is linked to ALT development via cGAS-STING DNA sensing pathway. Nat. Struct. Mol. Biol. 24:121124–31
     [Google Scholar]
  15. Chiba K, Johnson JZ, Vogan JM, Wagner T, Boyle JM, Hockemeyer D 2015. Cancer-associated TERT promoter mutations abrogate telomerase silencing. eLife 4:e07918
     [Google Scholar]
  16. Chiba K, Lorbeer FK, Shain AH, McSwiggen DT, Schruf E et al. 2017. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science 357:63581416–20
     [Google Scholar]
  17. Chin K, de Solorzano CO, Knowles D, Jones A, Chou W et al. 2004. In situ analyses of genome instability in breast cancer. Nat. Genet. 36:9984–88
     [Google Scholar]
  18. Chong L, van Steensel B, Broccoli D, Erdjument-Bromage H, Hanish J et al. 1995. A human telomeric protein. Science 270:52421663–67
     [Google Scholar]
  19. Clynes D, Jelinska C, Xella B, Ayyub H, Scott C et al. 2015. Suppression of the alternative lengthening of telomere pathway by the chromatin remodelling factor ATRX. Nat. Commun. 6:7538
     [Google Scholar]
  20. Conomos D, Reddel RR, Pickett HA 2014. NuRD–ZNF827 recruitment to telomeres creates a molecular scaffold for homologous recombination. Nat. Struct. Mol. Biol. 21:9760–70
     [Google Scholar]
  21. Conomos D, Stutz MD, Hills M, Neumann AA, Bryan TM et al. 2012. Variant repeats are interspersed throughout the telomeres and recruit nuclear receptors in ALT cells. J. Cell Biol. 199:6893–906
     [Google Scholar]
  22. Coppé J-P, Desprez P-Y, Krtolica A, Campisi J 2010. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5:99–118
     [Google Scholar]
  23. Coppé J-P, Kauser K, Campisi J, Beauséjour CM 2006. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J. Biol. Chem. 281:4029568–74
     [Google Scholar]
  24. Cortés-Ciriano I, Lee JJ-K, Xi R, Jain D, Jung YL et al. 2020. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nat. Genet. 52:3331–41
     [Google Scholar]
  25. Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW et al. 1992. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J 11:51921–29
     [Google Scholar]
  26. Counter CM, Botelho FM, Wang P, Harley CB, Bacchetti S 1994. Stabilization of short telomeres and telomerase activity accompany immortalization of Epstein-Barr virus-transformed human B lymphocytes. J. Virol. 68:53410–14
     [Google Scholar]
  27. Cristofari G, Lingner J. 2006. Telomere length homeostasis requires that telomerase levels are limiting. EMBO J 25:3565–74
     [Google Scholar]
  28. Cubiles MD, Barroso S, Vaquero-Sedas MI, Enguix A, Aguilera A, Vega-Palas MA 2018. Epigenetic features of human telomeres. Nucleic Acids Res 46:52347–55
     [Google Scholar]
  29. d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P et al. 2003. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:6963194–98
     [Google Scholar]
  30. Davoli T, de Lange T 2012. Telomere-driven tetraploidization occurs in human cells undergoing crisis and promotes transformation of mouse cells. Cancer Cell 21:6765–76
     [Google Scholar]
  31. De Cecco M, Ito T, Petrashen AP, Elias AE, Skvir NJ et al. 2019. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566:774273–78
     [Google Scholar]
  32. de Lange T. 2005. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19:182100–10
     [Google Scholar]
  33. de Lange T. 2018. Shelterin-mediated telomere protection. Annu. Rev. Genet. 52:1223–47
     [Google Scholar]
  34. Deckbar D, Birraux J, Krempler A, Tchouandong L, Beucher A et al. 2007. Chromosome breakage after G2 checkpoint release. J. Cell Biol. 176:6749–55
     [Google Scholar]
  35. Dilley RL, Greenberg RA. 2015. ALTernative telomere maintenance and cancer. Trends Cancer 1:2145–56
     [Google Scholar]
  36. Doksani Y, Wu JY, de Lange T, Zhuang X 2013. Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation. Cell 155:2345–56
     [Google Scholar]
  37. Dou Z, Ghosh K, Vizioli MG, Zhu J, Sen P et al. 2017. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550:7676402–6
     [Google Scholar]
  38. Dyer MA, Qadeer ZA, Valle-Garcia D, Bernstein E 2017. ATRX and DAXX: mechanisms and mutations. Cold Spring Harb. Perspect. Med. 7:3a026567
     [Google Scholar]
  39. Episkopou H, Draskovic I, Van Beneden A, Tilman G, Mattiussi M et al. 2014. Alternative lengthening of telomeres is characterized by reduced compaction of telomeric chromatin. Nucleic Acids Res 42:74391–405
     [Google Scholar]
  40. Erdel F, Kratz K, Willcox S, Griffith JD, Greene EC, de Lange T 2017. Telomere recognition and assembly mechanism of mammalian shelterin. Cell Rep 18:141–53
     [Google Scholar]
  41. Feng J, Funk WD, Wang SS, Weinrich SL, Avilion AA et al. 1995. The RNA component of human telomerase. Science 269:52281236–41
     [Google Scholar]
  42. Fouché N, Cesare AJ, Willcox S, Ozgür S, Compton SA, Griffith JD 2006. The basic domain of TRF2 directs binding to DNA junctions irrespective of the presence of TTAGGG repeats. J. Biol. Chem. 281:4937486–95
     [Google Scholar]
  43. Gauchier M, Kan S, Barral A, Sauzet S, Agirre E et al. 2019. SETDB1-dependent heterochromatin stimulates alternative lengthening of telomeres. Sci. Adv. 5:5eaav3673
     [Google Scholar]
  44. Glück S, Guey B, Gulen MF, Wolter K, Kang T-W et al. 2017. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 19:91061–70
     [Google Scholar]
  45. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A et al. 1999. Mammalian telomeres end in a large duplex loop. Cell 97:4503–14
     [Google Scholar]
  46. Grishchuk Y, Ginet V, Truttmann AC, Clarke PGH, Puyal J 2011. Beclin 1-independent autophagy contributes to apoptosis in cortical neurons. Autophagy 7:101115–31
     [Google Scholar]
  47. Gui X, Yang H, Li T, Tan X, Shi P et al. 2019. Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. Nature 567:7747262–66
     [Google Scholar]
  48. Hara E, Smith R, Parry D, Tahara H, Stone S, Peters G 1996. Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence. Mol. Cell. Biol. 16:3859–67
     [Google Scholar]
  49. Harley CB, Futcher AB, Greider CW 1990. Telomeres shorten during ageing of human fibroblasts. Nature 345:6274458–60
     [Google Scholar]
  50. Harley CB, Vaziri H, Counter CM, Allsopp RC 1992. The telomere hypothesis of cellular aging. Exp. Gerontol. 27:4375–82
     [Google Scholar]
  51. Hayashi MT, Cesare AJ, Fitzpatrick JAJ, Lazzerini-Denchi E, Karlseder J 2012. A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest. Nat. Struct. Mol. Biol. 19:4387–94
     [Google Scholar]
  52. Hayashi MT, Cesare AJ, Rivera T, Karlseder J 2015. Cell death during crisis is mediated by mitotic telomere deprotection. Nature 522:7557492–96
     [Google Scholar]
  53. Hayflick L. 1965. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37:614–36
     [Google Scholar]
  54. Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH et al. 2011. Altered telomeres in tumors with ATRX and DAXX mutations. Science 333:6041425
     [Google Scholar]
  55. Hemann MT, Strong MA, Hao LY, Greider CW 2001. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107:167–77
     [Google Scholar]
  56. Herbig U, Jobling WA, Chen BPC, Chen DJ, Sedivy JM 2004. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21CIP1, but not p16INK4a. Mol. Cell 14:4501–13
     [Google Scholar]
  57. Hoang SM, O'Sullivan RJ. 2020. Alternative lengthening of telomeres: building bridges to connect chromosome ends. Trends Cancer 6:3247–60
     [Google Scholar]
  58. Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A et al. 2013. TERT promoter mutations in familial and sporadic melanoma. Science 339:6122959–61
     [Google Scholar]
  59. Houghtaling BR, Cuttonaro L, Chang W, Smith S 2004. A dynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2. Curr. Biol. 14:181621–31
     [Google Scholar]
  60. Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA 2013. Highly recurrent TERT promoter mutations in human melanoma. Science 339:6122957–59
     [Google Scholar]
  61. Huschtscha LI, Holliday R. 1983. Limited and unlimited growth of SV40-transformed cells from human diploid MRC-5 fibroblasts. J. Cell Sci. 63:177–99
     [Google Scholar]
  62. Jacobs JJL, de Lange T 2004. Significant role for p16INK4a in p53-independent telomere-directed senescence. Curr. Biol. 14:242302–8
     [Google Scholar]
  63. Jones RE, Oh S, Grimstead JW, Zimbric J, Roger L et al. 2014. Escape from telomere-driven crisis is DNA ligase III dependent. Cell Rep 8:41063–76
     [Google Scholar]
  64. Kang T-W, Yevsa T, Woller N, Hoenicke L, Wuestefeld T et al. 2011. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479:7374547–51
     [Google Scholar]
  65. Karlseder J, Smogorzewska A, de Lange T 2002. Senescence induced by altered telomere state, not telomere loss. Science 295:55642446–49
     [Google Scholar]
  66. Kaul Z, Cesare AJ, Huschtscha LI, Neumann AA, Reddel RR 2012. Five dysfunctional telomeres predict onset of senescence in human cells. EMBO Rep 13:152–59
     [Google Scholar]
  67. Kim J, Sun C, Tran AD, Chin PJ, Ruiz PD et al. 2019. The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening. Nat. Struct. Mol. Biol. 26:3213–19
     [Google Scholar]
  68. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD et al. 1994. Specific association of human telomerase activity with immortal cells and cancer. Science 266:51932011–15
     [Google Scholar]
  69. Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J 2001. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. PNAS 98:2112072–77
     [Google Scholar]
  70. Law MJ, Lower KM, Voon HP, Hughes JR, Garrick D et al. 2010. ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner. Cell 143:3367–78
     [Google Scholar]
  71. Lee DD, Leao R, Komosa M, Gallo M, Zhang CH et al. 2019. DNA hypermethylation within TERT promoter upregulates TERT expression in cancer. J. Clin. Investig. 129:1223–29
     [Google Scholar]
  72. Letsolo BT, Rowson J, Baird DM 2010. Fusion of short telomeres in human cells is characterized by extensive deletion and microhomology, and can result in complex rearrangements. Nucleic Acids Res 38:61841–52
     [Google Scholar]
  73. Li B, de Lange T 2003. Rap1 affects the length and heterogeneity of human telomeres. Mol. Biol. Cell 14:125060–68
     [Google Scholar]
  74. Li F, Deng Z, Zhang L, Wu C, Jin Y et al. 2019. ATRX loss induces telomere dysfunction and necessitates induction of alternative lengthening of telomeres during human cell immortalization. EMBO J 38:19e96659
     [Google Scholar]
  75. Li Y, Schwab C, Ryan S, Papaemmanuil E, Robinson HM et al. 2014. Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia. Nature 508:749498–102
     [Google Scholar]
  76. Lin TT, Letsolo BT, Jones RE, Rowson J, Pratt G et al. 2010. Telomere dysfunction and fusion during the progression of chronic lymphocytic leukemia: evidence for a telomere crisis. Blood 116:111899–907
     [Google Scholar]
  77. Loayza D, De Lange T 2003. POT1 as a terminal transducer of TRF1 telomere length control. Nature 423:69431013–18
     [Google Scholar]
  78. Löbrich M, Jeggo PA. 2007. The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Nat. Rev. Cancer 7:11861–69
     [Google Scholar]
  79. Lovejoy CA, Li W, Reisenweber S, Thongthip S, Bruno J et al. 2012. Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLOS Genet 8:7e1002772
     [Google Scholar]
  80. Lovejoy CA, Takai K, Huh MS, Picketts DJ, de Lange T 2020. ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity. PLOS Biol 18:1e3000594
     [Google Scholar]
  81. Maciejowski J, Li Y, Bosco N, Campbell PJ, de Lange T 2015. Chromothripsis and kataegis induced by telomere crisis. Cell 163:71641–54
     [Google Scholar]
  82. Makarov VL, Hirose Y, Langmore JP 1997. Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening. Cell 88:5657–66
     [Google Scholar]
  83. Mardin BR, Drainas AP, Waszak SM, Weischenfeldt J, Isokane M et al. 2015. A cell-based model system links chromothripsis with hyperploidy. Mol. Syst. Biol. 11:9828
     [Google Scholar]
  84. Marzec P, Armenise C, Perot G, Roumelioti FM, Basyuk E et al. 2015. Nuclear-receptor-mediated telomere insertion leads to genome instability in ALT cancers. Cell 160:5913–27
     [Google Scholar]
  85. Maser RS, Wong K-K, Sahin E, Xia H, Naylor M et al. 2007. DNA-dependent protein kinase catalytic subunit is not required for dysfunctional telomere fusion and checkpoint response in the telomerase-deficient mouse. Mol. Cell. Biol. 27:62253–65
     [Google Scholar]
  86. McElligott R, Wellinger RJ. 1997. The terminal DNA structure of mammalian chromosomes. EMBO J 16:123705–14
     [Google Scholar]
  87. Montalto MC, Phillips JS, Ray FA 1999. Telomerase activation in human fibroblasts during escape from crisis. J. Cell. Physiol. 180:146–52
     [Google Scholar]
  88. Nassour J, Radford R, Correia A, Fusté JM, Schoell B et al. 2019. Autophagic cell death restricts chromosomal instability during replicative crisis. Nature 565:7741659–63
     [Google Scholar]
  89. Nguyen DT, Voon HPJ, Xella B, Scott C, Clynes D et al. 2017. The chromatin remodelling factor ATRX suppresses R-loops in transcribed telomeric repeats. EMBO Rep 18:6914–28
     [Google Scholar]
  90. Nikitina T, Woodcock CL. 2004. Closed chromatin loops at the ends of chromosomes. J. Cell Biol. 166:2161–65
     [Google Scholar]
  91. Nora GJ, Buncher NA, Opresko PL 2010. Telomeric protein TRF2 protects Holliday junctions with telomeric arms from displacement by the Werner syndrome helicase. Nucleic Acids Res 38:123984–98
     [Google Scholar]
  92. O'Connor MS, Safari A, Xin H, Liu D, Songyang Z 2006. A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. PNAS 103:3211874–79
     [Google Scholar]
  93. Olovnikov AM. 1973. A theory of marginotomy: the incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J. Theor. Biol. 41:1181–90
     [Google Scholar]
  94. O'Sullivan RJ, Almouzni G. 2014. Assembly of telomeric chromatin to create ALTernative endings. Trends Cell Biol 24:11675–85
     [Google Scholar]
  95. O'Sullivan RJ, Arnoult N, Lackner DH, Oganesian L, Haggblom C et al. 2014. Rapid induction of alternative lengthening of telomeres by depletion of the histone chaperone ASF1. Nat. Struct. Mol. Biol. 21:2167–74
     [Google Scholar]
  96. Palm W, de Lange T 2008. How shelterin protects mammalian telomeres. Annu. Rev. Genet. 42:301–34
     [Google Scholar]
  97. Peifer M, Hertwig F, Roels F, Dreidax D, Gartlgruber M et al. 2015. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature 526:7575700–4
     [Google Scholar]
  98. Poulet A, Buisson R, Faivre-Moskalenko C, Koelblen M, Amiard S et al. 2009. TRF2 promotes, remodels and protects telomeric Holliday junctions. EMBO J 28:6641–51
     [Google Scholar]
  99. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H et al. 2003. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Investig. 112:121809–20
     [Google Scholar]
  100. Rai R, Zheng H, He H, Luo Y, Multani A et al. 2010. The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres. EMBO J 29:152598–610
     [Google Scholar]
  101. Raices M, Verdun RE, Compton SA, Haggblom CI, Griffith JD et al. 2008. C. elegans telomeres contain G-strand and C-strand overhangs that are bound by distinct proteins. Cell 132:5745–57
     [Google Scholar]
  102. Ramamoorthy M, Smith S. 2015. Loss of ATRX suppresses resolution of telomere cohesion to control recombination in ALT cancer cells. Cancer Cell 28:3357–69
     [Google Scholar]
  103. Rao S, Tortola L, Perlot T, Wirnsberger G, Novatchkova M et al. 2014. A dual role for autophagy in a murine model of lung cancer. Nat. Commun. 5:3056
     [Google Scholar]
  104. Renaud S, Loukinov D, Abdullaev Z, Guilleret I, Bosman FT et al. 2007. Dual role of DNA methylation inside and outside of CTCF-binding regions in the transcriptional regulation of the telomerase hTERT gene. Nucleic Acids Res 35:41245–56
     [Google Scholar]
  105. Riboni R, Casati A, Nardo T, Zaccaro E, Ferretti L et al. 1997. Telomeric fusions in cultured human fibroblasts as a source of genomic instability. Cancer Genet. Cytogenet. 95:2130–36
     [Google Scholar]
  106. Roger L, Jones RE, Heppel NH, Williams GT, Sampson JR, Baird DM 2013. Extensive telomere erosion in the initiation of colorectal adenomas and its association with chromosomal instability. J. Natl. Cancer Inst. 105:161202–11
     [Google Scholar]
  107. Romanov SR, Kozakiewicz BK, Holst CR, Stampfer MR, Haupt LM, Tlsty TD 2001. Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes. Nature 409:6820633–37
     [Google Scholar]
  108. Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E et al. 2012. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:7384226–31
     [Google Scholar]
  109. Sfeir A, de Lange T 2012. Removal of shelterin reveals the telomere end-protection problem. Science 336:6081593–97
     [Google Scholar]
  110. Shay JW, Bacchetti S. 1997. A survey of telomerase activity in human cancer. Eur. J. Cancer 33:5787–91
     [Google Scholar]
  111. Shay JW, Pereira-Smith OM, Wright WE 1991. A role for both RB and p53 in the regulation of human cellular senescence. Exp. Cell Res. 196:133–39
     [Google Scholar]
  112. Smogorzewska A, de Lange T 2002. Different telomere damage signaling pathways in human and mouse cells. EMBO J 21:164338–48
     [Google Scholar]
  113. Smogorzewska A, Karlseder J, Holtgreve-Grez H, Jauch A, de Lange T 2002. DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2. Curr. Biol. 12:191635–44
     [Google Scholar]
  114. Stansel RM, de Lange T, Griffith JD 2001. T-loop assembly in vitro involves binding of TRF2 near the 3′ telomeric overhang. EMBO J 20:195532–40
     [Google Scholar]
  115. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR et al. 2011. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144:127–40
     [Google Scholar]
  116. Stewart SA, Ben-Porath I, Carey VJ, O'Connor BF, Hahn WC, Weinberg RA 2003. Erosion of the telomeric single-strand overhang at replicative senescence. Nat. Genet. 33:4492–96
     [Google Scholar]
  117. Takahashi A, Loo TM, Okada R, Kamachi F, Watanabe Y et al. 2018. Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells. Nat. Commun. 9:11242
     [Google Scholar]
  118. Takai H, Smogorzewska A, de Lange T 2003. DNA damage foci at dysfunctional telomeres. Curr. Biol. 13:171549–56
     [Google Scholar]
  119. Takai KK, Kibe T, Donigian JR, Frescas D, de Lange T 2011. Telomere protection by TPP1/POT1 requires tethering to TIN2. Mol. Cell 44:4647–59
     [Google Scholar]
  120. Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C et al. 2011. Autophagy-deficient mice develop multiple liver tumors. Genes Dev 25:8795–800
     [Google Scholar]
  121. Tanaka Y, Chen ZJ. 2012. STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci. Signal. 5:214ra20
     [Google Scholar]
  122. Valentijn LJ, Koster J, Zwijnenburg DA, Hasselt NE, van Sluis P et al. 2015. TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nat. Genet. 47:121411–14
     [Google Scholar]
  123. Van Ly D, Low RRJ, Frölich S, Bartolec TK, Kafer GR et al. 2018. Telomere loop dynamics in chromosome end protection. Mol. Cell 71:4510–25.e6
     [Google Scholar]
  124. Verhaak RGW, Bafna V, Mischel PS 2019. Extrachromosomal oncogene amplification in tumour pathogenesis and evolution. Nat. Rev. Cancer 19:5283–88
     [Google Scholar]
  125. Walen KH, Stampfer MR. 1989. Chromosome analyses of human mammary epithelial cells at stages of chemical-induced transformation progression to immortality. Cancer Genet. Cytogenet. 37:2249–61
     [Google Scholar]
  126. Watson JD. 1972. Origin of concatemeric T7DNA. Nat. New Biol. 239:94197–201
     [Google Scholar]
  127. White E, DiPaola RS. 2009. The double-edged sword of autophagy modulation in cancer. Clin. Cancer Res. 15:175308–16
     [Google Scholar]
  128. Wright WE, Shay JW. 1992. The two-stage mechanism controlling cellular senescence and immortalization. Exp. Gerontol. 27:4383–89
     [Google Scholar]
  129. Wright WE, Shay JW. 1995. Time, telomeres and tumours: Is cellular senescence more than an anticancer mechanism. ? Trends Cell Biol 5:8293–97
     [Google Scholar]
  130. Wu RA, Upton HE, Vogan JM, Collins K 2017. Telomerase mechanism of telomere synthesis. Annu. Rev. Biochem. 86:439–60
     [Google Scholar]
  131. Yang H, Wang H, Ren J, Chen Q, Chen ZJ 2017. cGAS is essential for cellular senescence. PNAS 114:23E4612–20
     [Google Scholar]
  132. Ye JZ-S, Hockemeyer D, Krutchinsky AN, Loayza D, Hooper SM et al. 2004. POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev 18:141649–54
     [Google Scholar]
  133. Yeager TR, Neumann AA, Englezou A, Huschtscha LI, Noble JR, Reddel RR 1999. Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body. Cancer Res 59:174175–79
     [Google Scholar]
  134. Yosef R, Pilpel N, Tokarsky-Amiel R, Biran A, Ovadya Y et al. 2016. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 7:11190
     [Google Scholar]
  135. Zhang JM, Yadav T, Ouyang J, Lan L, Zou L 2019. Alternative lengthening of telomeres through two distinct break-induced replication pathways. Cell Rep 26:4955–68.e3
     [Google Scholar]
  136. Zhao Y, Wang S, Popova EY, Grigoryev SA, Zhu J 2009. Rearrangement of upstream sequences of the hTERT gene during cellular immortalization. Genes Chromosomes Cancer 48:11963–74
     [Google Scholar]
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Telomeres and Cancer: Resolving the Paradox
Annual Review of Cancer Biology 5, 59 (2021); https://doi.org/10.1146/annurev-cancerbio-050420-023410
/content/journals/10.1146/annurev-cancerbio-050420-023410
/content/journals/10.1146/annurev-cancerbio-050420-023410
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  • Article Type: Review Article

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