Telomeres sustain the proliferative capacity of cells and maintain genome integrity by ensuring that chromosome ends are not mistaken for sites of DNA damage. Chromosome end protection is achieved by the telomeric shelterin complex, which suppresses DNA damage signalling and repair pathways.
In telomerase-negative cells, telomeres shorten during cell proliferation owing to incomplete DNA replication and exonucleolytic processing. This attrition compromises telomere function leading to signalling by the kinases ATM and ATR, cell cycle arrest and senescence or apoptosis.
Telomere attrition represents a major barrier to tumorigenesis, operating as a tumour suppressor pathway.
Loss of the RB and p53 pathways disables the ability of cells to arrest following ATR and ATM signalling at telomeres that were compromised by attrition.
RB-deficient and p53-deficient cells continue to experience telomere shortening, which leads to telomere crisis.
Telomere crisis can cause a wide array of genomic aberrations, including chromosome deletions and amplifications, translocations, chromothripsis, kataegis and tetraploidization.
Telomere crisis has been documented in many cancers, including chronic lymphocytic leukaemia, breast cancer and colorectal adenomas.
Activation of telomerase provides an escape from crisis and allows outgrowth of cells with a rearranged genome.
The shortening of human telomeres has two opposing effects during cancer development. On the one hand, telomere shortening can exert a tumour-suppressive effect through the proliferation arrest induced by activating the kinases ATM and ATR at unprotected chromosome ends. On the other hand, loss of telomere protection can lead to telomere crisis, which is a state of extensive genome instability that can promote cancer progression. Recent data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomere crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.
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Artandi, S. E. et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641–645 (2000). Demonstrates that telomere attrition in p53-mutant mice promotes epithelial cancers through the formation of chromosome rearrangements.
Artandi, S. E. & DePinho, R. A. Telomeres and telomerase in cancer. Carcinogenesis 31, 9–18 (2010).
Maciejowski, J., Li, Y., Bosco, N., Campbell, P. J. & de Lange, T. Chromothripsis and kataegis induced by telomere crisis. Cell 163, 1641–1654 (2015). Shows that dicentric chromosomes formed during telomere crisis persist through mitosis, are fragmented by TREX1 in G1 phase and give rise to chromothripsis and kataegis.
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Yates, L. R. & Campbell, P. J. Evolution of the cancer genome. Nat. Rev. Genet. 13, 795–806 (2012).
Willis, N. A., Rass, E. & Scully, R. Deciphering the code of the cancer genome: mechanisms of chromosome rearrangement. Trends Cancer 1, 217–230 (2015).
O'Hagan, R. C. et al. Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell 2, 149–155 (2002). Demonstrates that tumours with telomere dysfunction have higher levels of genome instability, with frequent amplifications and deletions.
Davoli, T., Denchi, E. L. & de Lange, T. Persistent telomere damage induces bypass of mitosis and tetraploidy. Cell 141, 81–93 (2010). Finds that persistent telomere dysfunction and consequent DNA damage signalling lead to bypass of mitosis and tetraploidization.
Davoli, T. & de Lange, T. Telomere-driven tetraploidization occurs in human cells undergoing crisis and promotes transformation of mouse cells. Cancer Cell 21, 765–776 (2012). Reports that telomere-driven tetraploidy occurs in human cells during telomere crisis.
de Lange, T. Telomere-related genome instability in cancer. Cold Spring Harb. Symp. Quant. Biol. 70, 197–204 (2005).
Blackburn, E. H. & Collins, K. Telomerase: an RNP enzyme synthesizes DNA. Cold Spring Harb. Perspect. Biol. 3, a003558 (2011).
Lingner, J. et al. Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 276, 561–567 (1997).
Hamma, T. & Ferré-D'Amaré, A. R. The box H/ACA ribonucleoprotein complex: interplay of RNA and protein structures in post-transcriptional RNA modification. J. Biol. Chem. 285, 805–809 (2010).
Nakamura, T. M. et al. Telomerase catalytic subunit homologs from fission yeast and human. Science 277, 955–959 (1997).
Meyerson, M. et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90, 785–795 (1997).
Feng, J. et al. The RNA component of human telomerase. Science 269, 1236–1241 (1995).
Egan, E. D. & Collins, K. Biogenesis of telomerase ribonucleoproteins. RNA 18, 1747–1759 (2012).
Darzacq, X. et al. Stepwise RNP assembly at the site of H/ACA RNA transcription in human cells. J. Cell Biol. 173, 207–218 (2006).
Kiss, T., Fayet-Lebaron, E. & Jády, B. E. Box H/ACA small ribonucleoproteins. Mol. Cell 37, 597–606 (2010).
Schmidt, J. C. & Cech, T. R. Human telomerase: biogenesis, trafficking, recruitment, and activation. Genes Dev. 29, 1095–1105 (2015).
Hockemeyer, D. & Collins, K. Control of telomerase action at human telomeres. Nat. Struct. Mol. Biol. 22, 848–852 (2015).
Shay, J. W. Role of telomeres and telomerase in aging and cancer. Cancer Discov. 6, 584–593 (2016).
Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998). Establishes a causal relationship between telomere shortening and cellular senescence.
Cristofari, G. & Lingner, J. Telomere length homeostasis requires that telomerase levels are limiting. EMBO J. 25, 565–574 (2006).
Chiba, K. et al. Cancer-associated TERT promoter mutations abrogate telomerase silencing. eLife 4, e07918 (2015).
Ramirez, R. D. et al. Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions. Genes Dev. 15, 398–403 (2001).
Vaziri, H. & Benchimol, S. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr. Biol. 8, 279–282 (1998).
Gomes, N. M. V. et al. Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination. Aging Cell 10, 761–768 (2011).
Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990). Demonstrates that the telomeres of human fibroblasts shorten during growth in culture.
Huffman, K. E., Levene, S. D., Tesmer, V. M., Shay, J. W. & Wright, W. E. Telomere shortening is proportional to the size of the G-rich telomeric 3′-overhang. J. Biol. Chem. 275, 19719–19722 (2000).
Miyake, Y. et al. RPA-like mammalian Ctc1–Stn1–Ten1 complex binds to single-stranded DNA and protects telomeres independently of the Pot1 pathway. Mol. Cell 36, 193–206 (2009).
Surovtseva, Y. V. et al. Conserved telomere maintenance component 1 interacts with STN1 and maintains chromosome ends in higher eukaryotes. Mol. Cell 36, 207–218 (2009).
Huang, C., Dai, X. & Chai, W. Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in. Cell Res. 22, 1681–1695 (2012).
Dai, X. et al. Molecular steps of G-overhang generation at human telomeres and its function in chromosome end protection. EMBO J. 29, 2788–2801 (2010).
Wu, P., Takai, H. & de Lange, T. Telomeric 3′ overhangs derive from resection by Exo1 and Apollo and fill-in by POT1b-associated CST. Cell 150, 39–52 (2012).
Wang, F. et al. Human CST has independent functions during telomere duplex replication and C-strand fill-in. Cell Rep. 2, 1096–1103 (2012).
Wu, P., van Overbeek, M., Rooney, S. & de Lange, T. Apollo contributes to G overhang maintenance and protects leading-end telomeres. Mol. Cell 39, 606–617 (2010).
Kasbek, C., Wang, F. & Price, C. M. Human TEN1 maintains telomere integrity and functions in genome-wide replication restart. J. Biol. Chem. 288, 30139–30150 (2013).
d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003). Finds that telomeres in senescent cells exhibit the hallmarks of DNA DSBs.
Zou, Y., Sfeir, A., Gryaznov, S. M., Shay, J. W. & Wright, W. E. Does a sentinel or a subset of short telomeres determine replicative senescence? Mol. Biol. Cell 15, 3709–3718 (2004).
Hemann, M. T., Strong, M. A., Hao, L. Y. & Greider, C. W. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107, 67–77 (2001).
Takai, H., Smogorzewska, A. & de Lange, T. DNA damage foci at dysfunctional telomeres. Curr. Biol. 13, 1549–1556 (2003).
Jacobs, J. J. L. & de Lange, T. Significant role for p16INK4a in p53-independent telomere-directed senescence. Curr. Biol. 14, 2302–2308 (2004).
Karlseder, J., Smogorzewska, A. & de Lange, T. Senescence induced by altered telomere state, not telomere loss. Science 295, 2446–2449 (2002).
Shay, J. W., Pereira-Smith, O. M. & Wright, W. E. A role for both RB and p53 in the regulation of human cellular senescence. Exp. Cell Res. 196, 33–39 (1991).
Hara, E., Tsurui, H., Shinozaki, A., Nakada, S. & Oda, K. 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. 179, 528–534 (1991).
Shay, J. W., Wright, W. E., Brasiskyte, D. & Van der Haegen, B. A. E6 of human papillomavirus type 16 can overcome the M1 stage of immortalization in human mammary epithelial cells but not in human fibroblasts. Oncogene 8, 1407–1413 (1993).
Brown, J. P., Wei, W. & Sedivy, J. M. Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277, 831–834 (1997).
Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999). Shows that p53 is activated during telomere crisis to induce growth arrest and suppress transformation.
Smogorzewska, A. & de Lange, T. Different telomere damage signaling pathways in human and mouse cells. EMBO J. 21, 4338–4348 (2002).
Greenberg, R. A. et al. Short dysfunctional telomeres impair tumorigenesis in the INK4aΔ2/3 cancer-prone mouse. Cell 97, 515–525 (1999).
Rudolph, K. L., Millard, M., Bosenberg, M. W. & DePinho, R. A. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat. Genet. 28, 155–159 (2001).
Qi, L. et al. Short telomeres and ataxia-telangiectasia mutated deficiency cooperatively increase telomere dysfunction and suppress tumorigenesis. Cancer Res. 63, 8188–8196 (2003).
Qi, L., Strong, M. A., Karim, B. O., Huso, D. L. & Greider, C. W. Telomere fusion to chromosome breaks reduces oncogenic translocations and tumour formation. Nat. Cell Biol. 7, 706–711 (2005).
Feldser, D. M. & Greider, C. W. Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell 11, 461–469 (2007).
Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994).
Huang, F. W. et al. Highly recurrent TERT promoter mutations in human melanoma. Science 339, 957–959 (2013). Uses whole-genome sequencing in melanomas to identify activating mutations in the TERT promoter.
Horn, S. et al. TERT promoter mutations in familial and sporadic melanoma. Science 339, 959–961 (2013). Identifies activating mutations in the TERT promoter through an analysis of melanoma-prone families.
Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).
Peifer, M. et al. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature 526, 700–704 (2015).
Valentijn, L. J. et al. TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nat. Genet. 47, 1411–1414 (2015).
Robles-Espinoza, C. D. et al. POT1 loss-of-function variants predispose to familial melanoma. Nat. Genet. 46, 478–481 (2014). Links germline, loss-of-function variants of POT1 to melanoma susceptibility and increased telomere length.
Shi, J. et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat. Genet. 46, 482–486 (2014). Reports the identification of unrelated, melanoma-prone families that carry variants of POT1 and show increased telomere lengths.
Pinzaru, A. M. et al. Telomere replication stress induced by POT1 inactivation accelerates tumorigenesis. Cell Rep. 15, 2170–2184 (2016).
Machiela, M. J. et al. Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: a report from the female lung cancer consortium in Asia. Int. J. Cancer 137, 311–319 (2015). Assesses telomere length using telomere length-associated single-nucleotide polymorphisms and finds that longer telomere length is associated with increased risk of non-Hodgkin lymphoma.
Machiela, M. J. et al. Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes. Hum. Mol. Genet. 25, 1663–1676 (2016).
Ojha, J. et al. Genetic variation associated with longer telomere length increases risk of chronic lymphocytic leukemia. Cancer Epidemiol. Biomarkers Prev. 25, 1043–1049 (2016). Shows that an inherited predisposition for longer telomeres is associated with an increased risk of CLL.
Mangino, M. et al. Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans. Hum. Mol. Genet. 21, 5385–5394 (2012).
Walsh, K. M. et al. Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk. Nat. Genet. 46, 731–735 (2014).
Rode, L., Nordestgaard, B. G. & Bojesen, S. E. Long telomeres and cancer risk among 95 568 individuals from the general population. Int. J. Epidemiol. 45, 1634–1643 (2016).
Hayashi, M. T., Cesare, A. J., Fitzpatrick, J. A. J., Lazzerini Denchi, E. & Karlseder, J. A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest. Nat. Struct. Mol. Biol. 19, 387–394 (2012).
Hayashi, M. T., Cesare, A. J., Rivera, T. & Karlseder, J. Cell death during crisis is mediated by mitotic telomere deprotection. Nature 522, 492–496 (2015).
Boboila, C., Alt, F. W. & Schwer, B. Classical and alternative end-joining pathways for repair of lymphocyte-specific and general DNA double-strand breaks. Adv. Immunol. 116, 1–49 (2012).
Smogorzewska, A., Karlseder, J., Holtgreve-Grez, H., Jauch, A. & de Lange, T. DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2. Curr. Biol. 12, 1635–1644 (2002).
Capper, R. et al. The nature of telomere fusion and a definition of the critical telomere length in human cells. Genes Dev. 21, 2495–2508 (2007).
Oh, S. et al. DNA ligase III and DNA ligase IV carry out genetically distinct forms of end joining in human somatic cells. DNA Repair 21, 97–110 (2014).
Lin, T. T. et al. Telomere dysfunction and fusion during the progression of chronic lymphocytic leukemia: evidence for a telomere crisis. Blood 116, 1899–1907 (2010). Shows that telomere shortening and fusions in CLL increase with advanced disease and correlate with large-scale genome rearrangements.
Jones, R. E. et al. Escape from telomere-driven crisis is DNA ligase III dependent. Cell Rep. 8, 1063–1076 (2014).
Maser, R. S. et al. 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, 2253–2265 (2007).
Roger, L. et al. Extensive telomere erosion in the initiation of colorectal adenomas and its association with chromosomal instability. J. Natl Cancer Inst. 105, 1202–1211 (2013).
Celli, G. B. & de Lange, T. DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion. Nat. Cell Biol. 7, 712–718 (2005).
Celli, G. B., Denchi, E. L. & de Lange, T. Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination. Nat. Cell Biol. 8, 885–890 (2006).
Riboni, R. et al. Telomeric fusions in cultured human fibroblasts as a source of genomic instability. Cancer Genet. Cytogenet. 95, 130–136 (1997).
McClintock, B. The behavior in successive nuclear divisions of a chromosome broken at meiosis. Proc. Natl Acad. Sci. USA 25, 405–416 (1939).
Gisselsson, D. et al. Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. Proc. Natl Acad. Sci. USA 97, 5357–5362 (2000).
Murnane, J. P. Telomeres and chromosome instability. DNA Repair 5, 1082–1092 (2006).
Llorente, B., Smith, C. E. & Symington, L. S. Break-induced replication: what is it and what is it for? Cell Cycle 7, 859–864 (2008).
Anand, R. P., Lovett, S. T. & Haber, J. E. Break-induced DNA replication. Cold Spring Harb. Perspect. Biol. 5, a010397 (2013).
Shih, I. M. et al. Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. Cancer Res. 61, 818–822 (2001).
Liddiard, K. et al. Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4. Genome Res. 26, 588–600 (2016). Uses single molecule analysis to demonstrate that a single dysfunctional telomere can fuse with diverse non-telomeric loci.
Li, Y. et al. Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia. Nature 508, 102 (2014). Uses whole-genome sequencing to show that, in leukaemia, dicentric chromosomes formed by telomere fusion or a Robertsonian translocation may precipitate chromothripsis.
Lo, A. W. I. et al. DNA amplification by breakage/fusion/bridge cycles initiated by spontaneous telomere loss in a human cancer cell line. Neoplasia 4, 531–538 (2002).
Ma, C., Martin, S., Trask, B. & Hamlin, J. L. Sister chromatid fusion initiates amplification of the dihydrofolate reductase gene in Chinese hamster cells. Genes Dev. 7, 605–620 (1993).
Smith, K. A., Gorman, P. A., Stark, M. B., Groves, R. P. & Stark, G. R. Distinctive chromosomal structures are formed very early in the amplification of CAD genes in Syrian hamster cells. Cell 63, 1219–1227 (1990).
Bignell, G. R. et al. Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution. Genome Res. 17, 1296–1303 (2007).
Campbell, P. J. et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467, 1113 (2010).
Waddell, N. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015).
Nones, K. et al. Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis. Nat. Commun. 5, 5224 (2014).
Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011). Reports the discovery of chromothripsis using next-generation sequencing.
Rausch, T. et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148, 59–71 (2012).
Jones, M. J. K. & Jallepalli, P. V. Chromothripsis: chromosomes in crisis. Dev. Cell 23, 917 (2012).
Garsed, D. W. et al. The architecture and evolution of cancer neochromosomes. Cancer Cell 26, 653–667 (2014).
Lopez, V. et al. Cytokinesis breaks dicentric chromosomes preferentially at pericentromeric regions and telomere fusions. Genes Dev. 29, 322–336 (2015).
Pampalona, J. et al. Chromosome bridges maintain kinetochore–microtubule attachment throughout mitosis and rarely break during anaphase. PLoS ONE 11, e0147420 (2016).
Vargas, J. D., Hatch, E. M., Anderson, D. J. & Hetzer, M. W. Transient nuclear envelope rupturing during interphase in human cancer cells. Nucleus 3, 88–100 (2012).
Hatch, E. M., Fischer, A. H., Deerinck, T. J. & Hetzer, M. W. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell 154, 47–60 (2013).
Guelen, L. et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453, 948–951 (2008).
Raab, M. et al. ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death. Science 352, 7611–7362 (2016).
Denais, C. M. et al. Nuclear envelope rupture and repair during cancer cell migration. Science 352, 1–8 (2016).
Lindahl, T., Gally, J. A. & Edelman, G. M. Properties of deoxyribonuclease 3 from mammalian tissues. J. Biol. Chem. 244, 5014–5019 (1969).
Höss, M. et al. A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD protein. EMBO J. 18, 3868–3875 (1999).
Mazur, D. J. & Perrino, F. W. Structure and expression of the TREX1 and TREX2 3′−5′ exonuclease genes. J. Biol. Chem. 276, 14718–14727 (2001).
Rice, G. I., Rodero, M. P. & Crow, Y. J. Human disease phenotypes associated with mutations in TREX1. J. Clin. Immunol. 35, 235–243 (2015).
Gisselsson, D. et al. Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc. Natl Acad. Sci. USA 98, 12683–12688 (2001).
Crasta, K. et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature 482, 53–58 (2012).
Zhang, C.-Z. et al. Chromothripsis from DNA damage in micronuclei. Nature 522, 179–184 (2015).
Santaguida, S., Tighe, A., D'Alise, A. M., Taylor, S. S. & Musacchio, A. Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine. J. Cell Biol. 190, 73–87 (2010).
Mardin, B. R. et al. A cell-based model system links chromothripsis with hyperploidy. Mol. Syst. Biol. 11, 828–828 (2015).
Nik-Zainal, S. et al. Mutational processes molding the genomes of 21 breast cancers. Cell 149, 979–993 (2012).
Roberts, S. A. et al. Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Mol. Cell 46, 424–435 (2012).
Roberts, S. A. et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat. Genet. 45, 970–976 (2013).
Chan, K. et al. An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers. Nat. Genet. 47, 1067–1072 (2015).
Harris, R. S., Petersen-Mahrt, S. K. & Neuberger, M. S. RNA editing enzyme APOBEC1 and some of its homologs can act as DNA mutators. Mol. Cell 10, 1247–1253 (2002).
Harris, R. S. & Dudley, J. P. APOBECs and virus restriction. Virology 480, 131–145 (2015).
Davoli, T. & de Lange, T. The causes and consequences of polyploidy in normal development and cancer. Annu. Rev. Cell Dev. Biol. 27, 585–610 (2011).
Shackney, S. E. et al. Model for the genetic evolution of human solid tumors. Cancer Res. 49, 3344–3354 (1989).
Galipeau, P. C. et al. 17p (p53) allelic losses, 4N (G2/tetraploid) populations, and progression to aneuploidy in Barrett's esophagus. Proc. Natl Acad. Sci. USA 93, 7081–7084 (1996).
Olaharski, A. J. et al. Tetraploidy and chromosomal instability are early events during cervical carcinogenesis. Carcinogenesis 27, 337–343 (2006).
Zack, T. I. et al. Pan-cancer patterns of somatic copy number alteration. Nat. Genet. 45, 1134–1140 (2013).
Nguyen, H. G. et al. Deregulated Aurora-B induced tetraploidy promotes tumorigenesis. FASEB J. 23, 2741–2748 (2009).
Duelli, D. M. et al. A virus causes cancer by inducing massive chromosomal instability through cell fusion. Curr. Biol. 17, 431–437 (2007).
Ganem, N. J., Storchová, Z. & Pellman, D. Tetraploidy, aneuploidy and cancer. Curr. Opin. Genet. Dev. 17, 157–162 (2007).
Fujiwara, T. et al. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437, 1043–1047 (2005).
Dewhurst, S. M. et al. Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution. Cancer Discov. 4, 175–185 (2014).
de Lange, T. et al. Structure and variability of human chromosome ends. Mol. Cell. Biol. 10, 518–527 (1990).
Hastie, N. D. et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature 346, 866–868 (1990).
Furugori, E. et al. Telomere shortening in gastric carcinoma with aging despite telomerase activation. J. Cancer Res. Clin. Oncol. 126, 481–485 (2000).
Mehle, C., Ljungberg, B. & Roos, G. Telomere shortening in renal cell carcinoma. Cancer Res. 54, 236–241 (1994).
Takagi, S. et al. Telomere shortening and the clinicopathologic characteristics of human colorectal carcinomas. Cancer 86, 1431–1436 (1999).
Sommerfeld, H. J. et al. Telomerase activity: a prevalent marker of malignant human prostate tissue. Cancer Res. 56, 218–222 (1996).
Meeker, A. K. et al. Telomere shortening is an early somatic DNA alteration in human prostate tumorigenesis. Cancer Res. 62, 6405–6409 (2002).
Meeker, A. K. et al. Telomere length abnormalities occur early in the initiation of epithelial carcinogenesis. Clin. Cancer Res. 10, 3317–3326 (2004).
Clarke, D. J., Johnson, R. T. & Downes, C. S. Topoisomerase II inhibition prevents anaphase chromatid segregation in mammalian cells independently of the generation of DNA strand breaks. J. Cell Sci. 105, 563–569 (1993).
Hauf, S., Waizenegger, I. C. & Peters, J. M. Cohesin cleavage by separase required for anaphase and cytokinesis in human cells. Science 293, 1320–1323 (2001).
Chin, K. et al. In situ analyses of genome instability in breast cancer. Nat. Genet. 36, 984–988 (2004).
O'Connell, P. et al. Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci. J. Natl Cancer Inst. 90, 697–703 (1998).
Meeker, A. K. et al. Telomere shortening occurs in subsets of normal breast epithelium as well as in situ and invasive carcinoma. Am. J. Pathol. 164, 925–935 (2004).
Herbert, B. S., Wright, W. E. & Shay, J. W. Telomerase and breast cancer. Breast Cancer Res. 3, 146–149 (2001).
Baird, D. M., Rowson, J., Wynford-Thomas, D. & Kipling, D. Extensive allelic variation and ultrashort telomeres in senescent human cells. Nat. Genet. 33, 203–207 (2003).
Tanaka, H. et al. Telomere fusions in early human breast carcinoma. Proc. Natl Acad. Sci. USA 109, 14098–14103 (2012).
Lin, T. T. et al. Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease. Br. J. Haematol. 167, 223 (2014).
Simpson, K. et al. Telomere fusion threshold identifies a poor prognostic subset of breast cancer patients. Mol. Oncol. 9, 1186–1193 (2015).
Heidenreich, B., Rachakonda, P. S., Hemminki, K. & Kumar, R. TERT promoter mutations in cancer development. Curr. Opin. Genet. Dev. 24, 30–37 (2014).
Killela, P. J. et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc. Natl Acad. Sci. USA 110, 6026 (2013).
Kinde, I. et al. TERT promoter mutations occur early in urothelial neoplasia and are biomarkers of early disease and disease recurrence in urine. Cancer Res. 73, 7162–7167 (2013).
Remke, M. et al. TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma. Acta Neuropathol. 126, 917–929 (2013).
Quaas, A. et al. Frequency of TERT promoter mutations in primary tumors of the liver. Virchows Arch. 465, 673–677 (2014).
Weinhold, N., Jacobsen, A., Schultz, N., Sander, C. & Lee, W. Genome-wide analysis of noncoding regulatory mutations in cancer. Nat. Genet. 46, 1160–1165 (2014).
Borah, S. et al. TERT promoter mutations and telomerase reactivation in urothelial cancer. Science 347, 1006–1010 (2015).
Bell, R. J. A. et al. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science 348, 1036–1039 (2015).
Pickett, H. A. & Reddel, R. R. Molecular mechanisms of activity and derepression of alternative lengthening of telomeres. Nat. Struct. Mol. Biol. 22, 875–880 (2015).
Lovejoy, C. A. et al. Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet. 8, e1002772 (2012).
Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).
Heaphy, C. M. et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science 333, 425 (2011).
Heaphy, C. M. et al. Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Am. J. Pathol. 179, 1608–1615 (2011).
Ceccarelli, M. et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164, 550–563 (2016).
Eckel-Passow, J. E. et al. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N. Engl. J. Med. 372, 2499–2508 (2015).
Ding, Z. et al. Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases. Cell 148, 896–907 (2012).
Sprung, C. N., Sabatier, L. & Murnane, J. P. Telomere dynamics in a human cancer cell line. Exp. Cell Res. 247, 29–37 (1999).
Fouladi, B., Sabatier, L., Miller, D., Pottier, G. & Murnane, J. P. The relationship between spontaneous telomere loss and chromosome instability in a human tumor cell line. Neoplasia 2, 540–554 (2000).
Murnane, J. P., Sabatier, L., Marder, B. A. & Morgan, W. F. Telomere dynamics in an immortal human cell line. EMBO J. 13, 4953–4962 (1994).
Sabatier, L., Ricoul, M., Pottier, G. & Murnane, J. P. The loss of a single telomere can result in instability of multiple chromosomes in a human tumor cell line. Mol. Cancer Res. 3, 139–150 (2005).
Gascoigne, K. E. & Cheeseman, I. M. Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis. Chromosome Res. 21, 407–418 (2013).
Baca, S. C. et al. Punctuated evolution of prostate cancer genomes. Cell 153, 666–677 (2013).
Palm, W. & de Lange, T. How shelterin protects mammalian telomeres. Annu. Rev. Genet. 42, 301–334 (2008).
Schmutz, I. & de Lange, T. Shelterin. Curr. Biol. 26, R397–R399 (2016).
Lazzerini Denchi, E. & Sfeir, A. Stop pulling my strings — what telomeres taught us about the DNA damage response. Nat. Rev. Mol. Cell Biol. 17, 364–378 (2016).
Xin, H. et al. TPP1 is a homologue of ciliate TEBP-β and interacts with POT1 to recruit telomerase. Nature 445, 559–562 (2007).
Nandakumar, J. et al. The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature 492, 285–289 (2013).
Nandakumar, J. & Cech, T. R. Finding the end: recruitment of telomerase to telomeres. Nat. Rev. Mol. Cell Biol. 14, 69–82 (2013).
Sexton, A. N. et al. Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation. Genes Dev. 28, 1885–1899 (2014).
Abreu, E. et al. TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo. Mol. Cell. Biol. 30, 2971–2982 (2010).
Frank, A. K. et al. The shelterin TIN2 subunit mediates recruitment of telomerase to telomeres. PLoS Genet. 11, e1005410 (2015).
Greider, C. W. Regulating telomere length from the inside out: the replication fork model. Genes Dev. 30, 1483–1491 (2016).
Smogorzewska, A. & de Lange, T. Regulation of telomerase by telomeric proteins. Annu. Rev. Biochem. 73, 177–208 (2004).
The authors thank S. Yu and the de Lange laboratory for discussions and help with this manuscript. The authors' work is supported by grants from the US National Institutes of Health (CA181090, AG016642 and K99CA212290), the STARR Cancer Consortium and the Breast Cancer Research Foundation.
The authors declare no competing financial interests.
A PI3K-related protein kinase that initiates the response to double-strand breaks, with crucial roles in cell cycle regulation and DNA repair.
A PI3K-related protein kinase that responds to the formation of single-stranded DNA, with a crucial role in the response to replication stress and double-strand breaks.
- Non-homologous end joining
A major double-strand break repair pathway that does not rely on sequence homology and can result in small insertions and deletions at the site of repair.
- Hayflick limit
The finite proliferation potential of primary human cells.
- Dicentric chromosomes
Abnormal chromosomes with two centromeres that can result from telomere–telomere fusion.
- Break-induced replication
An origin of replication-independent replication restart that is initiated by the invasion of resected DNA into homologous sequences.
Abnormal, small nuclei containing one or more chromosome (fragments); often formed as a result of mitotic chromosome segregation defects.
An intermediate filament protein that imparts structural rigidity to the nucleus by assembling into a meshwork at the inner nuclear membrane.
- Hyper-triploid karyotype
A genome that contains more than three (3N) but less than four (4N) sets of chromosomes.
- Anaphase bridges
DNA bridges that connect chromatin masses undergoing separation during anaphase and can be observed with conventional DNA staining techniques.
- Usual ductal hyperplasia
A benign overgrowth of cells that line the ducts or milk glands and is associated with an elevated risk of breast cancer.
- Ductal carcinoma in situ
A noninvasive, early form of breast cancer characterized by proliferative, malignant cells that are confined to the milk duct.
- Alternative lengthening of telomeres
A telomere lengthening mechanism that relies on homologous recombination-mediated DNA copying to counteract telomere shortening.
A class of complex DNA rearrangements frequently observed in prostate cancer, which is characterized by multiple chromatin rearrangements that arise in a highly interdependent manner.
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Maciejowski, J., de Lange, T. Telomeres in cancer: tumour suppression and genome instability. Nat Rev Mol Cell Biol 18, 175–186 (2017). https://doi.org/10.1038/nrm.2016.171
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