2009 Nobel Prize in Physiology or Medicine: telomeres and telomerase

Subjects

Elizabeth H Blackburn, Carol W Greider and Jack W Szostak were acknowledged with this year's Nobel Prize in Physiology or Medicine for their discoveries on how chromosomes are protected by telomeres and the enzyme telomerase.

In the first half of the twentieth century, classic studies by Hermann Müller (Nobel Prize 1945) working with the fruit fly (Drosophila melanogaster) and by Barbara McClintock (Nobel Prize 1983) studying maize (Zea Mays) proposed the existence of a special structure at the chromosome ends (Müller, 1938; McClintock, 1939). This structure would have the essential role of protecting chromosome ends from fusing to each other, thus ensuring the correct segregation of the genetic material into daughter cells during every cell division cycle. Such structures, which Müller called telomeres (from the Greek telos ‘end’ and meros ‘part’), conferred identity to the ends of chromosomes such that the cell could distinguish between native chromosome ends and the DNA fragments resulting from double-strand breaks, which must be fused back together to safeguard the integrity of the genetic material (McClintock, 1941). This protective function of telomeres is known as ‘telomere capping’. The molecular mechanisms underlying telomere capping involve specialized protein complexes bound to telomeres (Blackburn, 2000, 2001, 2005; Blackburn et al., 2006) as well as telomere-associated noncoding RNAs known as TERRA (reviewed by Schoeftner and Blasco, 2009a, 2009b; Luke and Lingner, 2009). If telomere capping is disrupted, telomere fusions generate dicentric chromosomes that are susceptible to breakage during mitosis, ultimately leading to aneuploidy and disease states including premature aging pathologies and cancer (Hackett et al., 2001; Hackett and Greider, 2002).

In 1961, Leonard Hayflick discovered that human cells could undergo only a limited number of cell divisions when cultured in vitro (Hayflick and Moorhead, 1961), a phenomenon known as replicative senescence or the Hayflick limit (reviewed by Hayflick, 1998). In fact, this is another feature of telomeres; their length determines the number of cell divisions that a cell can undertake. Alexei Olovnikov linked the Hayflick limit to the replication of telomeric DNA (Olovnikov, 1971, 1973). Replication of the 5′-3′ strand requires RNA primers that are removed afterward, leaving gaps. These gaps are filled-in using the adjacent Okazaki fragments as primers. The very terminal gap at the 5′ end of telomeres cannot be filled because of the lack of such a primer. Olovnikov proposed that the DNA replication machinery could not copy chromosomal ends completely and, therefore, cells could not compensate for the chromosomal shortening produced associated with cell division, suggesting that progressive telomere shortening may be a key factor to limit the number of cell divisions. James D Watson (Nobel Prize 1962) also recognized that the unidirectional nature of DNA replication was a problem for the complete copy of chromosomal ends (Watson, 1972). This was called the ‘end-replication problem’. In this manner, during each cycle of cell division, a small fragment of telomeric DNA is lost from the end. After several rounds of division, telomeres eventually reach a critically short length, which activates the pathways for senescence and cell death (Hermann et al., 2001; Samper et al., 2001).

Uncovering the solution to the end-replication problem took several years of intense research. In the 1970s, several models speculated that chromosome ends contained inverted repeats, which would generate hairpins and intermediate replicative structures, able to bypass the end-replication problem (Cavalier-Smith, 1974; Bateman, 1975; Dancis and Holmquist, 1979). In 1978, Blackburn and Gall showed that the telomeres of the ciliated-protozoan Tetrahymena thermophila comprised a hexanucleotide tandomly repeated sequence (IndexTermCCCCTT), which was variable in length (Blackburn and Gall, 1978). Tetrahymena had a number of advantages for the study of telomeres, among them that it contained linear (and circular) extrachromosomal rDNA molecules with palindromic termini, which were replicated in the cell nucleus. In addition, these terminal sequences were well characterized (Blackburn and Gall, 1978). For these reasons, Blackburn and her collaborator Szostak decided to further use it for their studies. They showed that the terminal-repeated sequence of Tetrahymena could protect a linear plasmid from degradation in yeast. Thus, these repeated sequences conferred telomere function. In addition, they showed that hairpin structures alone were not sufficient to provide telomere function (Szostak and Blackburn, 1982). Importantly, their discoveries also indicated that the structural properties of telomere function were evolutionarily conserved from yeast to Tetrahymena (Fungi to Animalia kingdoms, respectively).

Blackburn had shown that Tetrahymena telomeres varied in length (Blackburn and Gall, 1978) and that they could be lengthened when cells were grown long term in logarithmic phase. Moreover, this lengthening of the telomeres was always attributable to an increase in the number of hexanucleotides repeats. Blackburn and co-workers reasoned that the conventional replication system was not likely responsible for the extra addition of telomere repeats and that recombination was not required for telomere lengthening (Dunn et al., 1984). On the basis of these considerations, they proposed that telomere replication should involve a terminal transferase-like activity able to add telomeric repeats onto chromosome ends de novo (Shampay et al., 1984). In 1985, Carol W Greider, a PhD student working in Blackburn's laboratory, first showed the existence of a transferase-like activity in Tetrahymena cell-free extracts, which accurately added telomere repeats de novo onto chromosome ends (Greider and Blackburn, 1985). Two years later, Greider and Blackburn (1987) purified the enzyme and showed that it was a ribonucleoprotein complex, being both components (RNA and protein) required for activity. Thus, they had discovered a new type of DNA polymerase, which they called telomerase. Cloning of the Tetrahymena telomerase RNA component in 1989 further suggested that it contained the template for the addition of repeats onto telomeres (Greider and Blackburn, 1989). Thus, telomerase was a new type of reverse transcriptase, specialized in telomere replication. Although most of these discoveries were made in the very unusual organism Tetrahymena, we now know that the enzyme telomerase is the main mechanism used to elongate telomeres throughout the eukaryotes. This mechanism is widely conserved among higher eukaryotes, with the exception of D. melanogaster, whose chromosome ends consist of small retrotransposons (Pardue and DeBaryshe, 2003; Chan and Blackburn, 2004). Mutation of telomerase components in yeast (Lundblad and Szostak, 1989) first showed that telomerase was responsible for telomere length maintenance in this organism. Later on, generation of the first knockout mice for the telomerase RNA component (Blasco et al., 1997) showed a conserved role for telomerase as the main activity responsible for maintaining telomere length in mammals, and further uncovered its importance in tissue renewal and organismal life span. In the absence of telomerase, mice suffered an accelerated rate of telomere shortening associated with mouse aging, which led to premature development of age-associated pathologies and a reduced longevity (Lee et al., 1998; Herrera et al., 1999). Indeed, telomerase-deficient mice could only be bred for a limited number of generations, showing the essential function of telomerase for the maintenance of the species. Interestingly, in the absence of telomerase, both yeast and cultured mammalian cells can maintain telomeres through activation of alternative mechanisms based on recombination, also known as ALT in mammalian cells (Bryan and Reddel, 1997); however, ALT is not sufficient to grant organismal fitness and species propagation in mammals.

Very similar to Tetrahymena telomeres (formed by tandem repeats of the IndexTermTTTGGG sequence), vertebrate telomeres consist of IndexTermTTAGGG repeats, which end in a 3′ overhang of the G-rich strand. In turn, telomeric repeats are bound by a six-protein complex known as shelterin, whose components have functions in chromosome protection and control of telomere length (De Lange, 2005). Proper telomere function requires a minimal telomere length, the integrity of the shelterin complex, and a higher-order DNA structure called the T-loop, which is proposed to protect the 3′ overhang from degradation and DNA repair activities (Griffith et al., 1999; Blackburn, 2001; de Lange, 2005; Blasco, 2005). In addition, early studies with yeast showed that telomeres are able to create a repressive chromatin environment able to silence nearby genes, a phenomenon known as ‘telomere position effect’ (Gottschling et al., 1990; Palladino et al., 1993; Cooper et al., 1997), suggesting analogies with other silenced chromatin domains in the genome. Telomere position effect was later shown to operate in higher eukaryotes (Baur et al., 2001). More recently, mammalian telomeric and subtelomeric regions were found to be enriched in repressive histone modifications and heterochromatin protein 1 binding, whereas subtelomeric DNA was found to be densely methylated (reviewed by Blasco, 2007). These heterochromatic marks are proposed to negatively control telomere length and telomere recombination (reviewed by Blasco, 2007; Schoeftner and Blasco, 2009). In particular, decreased heterochromatin protein 1 binding to telomeres, as well as a decrease in the density of trimethylation of histone 3 at lysine 9 and trimethylation of lysine 20 of histone 4 in cells deficient for the Suv39 H1 and H2 histone methyltransferases, leads to substantial telomere elongation (Garcia-Cao et al., 2004). Furthermore, loss of subtelomeric DNA methylation also results in telomere length increase (Gonzalo et al., 2006). In both studies, the loss of repressive marks correlated with increased recombination rates, suggesting that heterochromatic marks prevent promiscuous telomere-recombination events and control telomere length. In addition to being enriched in heterochromatic marks, telomeres are bound by telomere-associated noncoding RNAs called TelRNAs or TERRAs (Azzalin et al., 2007; Azzalin and Lingner, 2008; Schoeftner and Blasco, 2008, 2009a, 2009b), which have been proposed to exert a negative control over telomere length based on their ability to behave as potent telomerase inhibitors in vitro (Schoeftner and Blasco, 2008).

Telomerase activity is undetectable in somatic tissues, except in stem cell compartments (reviewed by Flores et al., 2006), but the level of activity is not sufficient to prevent telomere shortening associated with cell division, tissue renewal and age as first shown by Harley et al. (1990). Because telomeres are necessary for genome integrity, their shortening was also proposed to cause cell senescence or apoptosis in the so-called ‘telomere hypothesis’ (Harley et al., 1990). Confirmation for this hypothesis in in vitro cultured cells came when reintroduction of the TERT telomerase catalytic component into telomerase-negative primary human cells was sufficient to bypass replicative senescence (or the Hayflick limit) and to confer immortal growth (Bodnar et al., 1998). In addition, the generation of the telomerase knockout mice showed in vivo that short telomeres could cause multiple organismal defects associated with decreased adult stem cell functionality (Blasco et al., 1997; Lee et al., 1998; Herrera et al., 1999; Flores et al., 2005; Hao et al., 2005). These organismal defects were more pronounced with each following generation, known as ‘genetic anticipation’. Interestingly, some patients characterized by poor telomere maintenance due to mutations in telomerase components (for example, dyskeratosis congenita, aplastic anemia, pulmonary fibrosis) also show disease anticipation (Mitchell et al., 1999; Collins and Mitchell, 2002; Mason et al., 2005), highlighting the similar phenotypes associated with telomere dysfunction in mice and humans.

All these findings gave rise to the interesting idea that increasing telomerase activity in somatic cells could have a positive effect, enlarging the life span of the organism. The generation of three mouse models with increased telomerase activity showed a greater susceptibility than wild-type to tumor formation, with a higher rate of mortality (Gonzalez-Suarez et al., 2001; Artandi et al., 2002; Canela et al., 2004), in agreement with telomere shortening representing a barrier for the uncontrolled growth of cancer cells. Interestingly, these mice also showed improved tissue regeneration and those that did not develop tumors displayed an increased life span (González-Suárez et al., 2005). Particularly, overexpression of the telomerase catalytic component TERT increased the capacity of epidermal stem cells to regenerate skin and hair (Flores et al., 2005; Sarin et al., 2005). However, the function of telomerase in organismal aging remained elusive until recently, in part due to the cancer-promoting activity of telomerase. To circumvent this problem, Blasco and co-workers constitutively expressed TERT in mice engineered to be cancer-resistant by means of enhanced expression of the tumor suppressors p53, p16 and p19ARF. In this context, TERT overexpression improved the fitness of tissues and produced a systemic delay in aging accompanied by extension of the median life span (Tomás-Loba et al., 2009). These results showed that constitutive expression of Tert provides anti-aging activity in the context of the organism.

Short telomeres are a barrier for cell division; therefore, it is not surprising that most cancer cells activate telomerase during tumorigenesis to maintain a minimum telomere length, even if telomeres are not lengthened (Counter et al., 1994; Kim et al., 1994, Harley, 2008). Indeed, some human tumors show amplification of both telomerase genes, TERC and TERT, suggesting that telomerase supports tumor growth, allowing cells with oncogenic mutations to divide (Kolquist et al., 1998; McKay et al., 2008; Rafnar et al., 2009; Shete et al., 2009; Stacey et al., 2009). Conversely, the lack of telomerase activity in most somatic cells works as a tumor suppressor mechanism. Furthermore, telomerase inhibition stops cancer cell growth (Li et al., 2005) and telomerase knockout mice with short telomeres are resistant to carcinogenesis (González-Suárez et al., 2000) even in backgrounds with higher susceptibility to tumor emergence, such as mice defective for INK4a/Arf, p21, ATM, Ku, DNAPK or PMS2 (Greenberg et al., 1999; Wong et al., 2003; Espejel et al., 2004; Choudhury et al., 2007; Siegl-Cachedenier et al., 2007). Nonetheless, primary cells from telomerase-deficient mice can also form tumors, maintaining their telomere length by recombinational mechanisms (Blasco, 2007; Hande et al., 1999; Herrera et al., 2000; Morrish and Greider, 2009). Interestingly, increasing evidence supports the link between stem cell biology and cancer, as some cancers emerge from transformation of normal stem cells (Bell and Van Zant, 2004; Blasco, 2005; Flores et al., 2005).

Recently, a further link between telomere biology and cancer was made by showing that subtelomeric regions are normally hypomethylated in human cancer cells and that this epigenetic defect influences both telomere length and telomere recombination (Vera et al., 2008). These findings indicate that epigenetic status of telomeres is altered during tumorigenesis, thus influencing telomere maintenance mechanisms in cancer cells. In addition to hypomethylation of subtelomeric DNA, many human cancers show decreased levels of telomere-associated TERRA (Schoeftner and Blasco, 2008), something that has been proposed to favor telomere elongation based on the observations that TERRA are potent telomerase inhibitors in vitro (Schoeftner and Blasco, 2008).

In summary, the early discoveries on telomere structure and function by Blackburn, Greider and Szostak unveiled a route to understanding the molecular bases underlying aging, stem cell biology, cancer and other human diseases. These topics remain of much interest and under intense investigation. Since those days, Elizabeth H Blackburn (professor at the University of California, San Francisco) and Carol W Greider (professor in the Johns Hopkins University of School of Medicine in Baltimore) continue studying the pathways that control telomere maintenance, function and its impact in human health and disease. Jack W Szostak (professor at Massachusetts General Hospital in Boston) switched focus to the fascinating question of the origin of life. He investigates threose nucleic acid molecules, progenitors of RNA and ‘steady-state’ replication, as well as the primitive formation of cell compartments, cell growth and cell division.

References

  1. Artandi SE, Alson S, Tietze MK, Sharpless NE, Ye S, Greenberg RA et al. (2002). Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc Natl Acad Sci USA 99: 8191–8196.

  2. Azzalin CM, Lingner J . (2008). Telomeres: the silence is broken. Cell Cycle 7: 1161–1165.

  3. Azzalin CM, Reichenbach P, Khoriauli L, Giulotta E, Lingner J . (2007). Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science 318: 798–801.

  4. Bateman AJ . (1975). Letter: simplification of palindromic telomere theory. Nature 253: 379–380.

  5. Baur JA, Zou Y, Shay JW, Wright WE . (2001). Telomere position effect in human cells. Science 292: 2075–2077.

  6. Bell DR, Van Zant G . 2004. Stem cells, aging, and cancer: inevitabilities and outcomes. Oncogene 23: 7290–7296.

  7. Blackburn EH . (2000). Telomere states and cell fates. Nature 408: 53–56.

  8. Blackburn EH . (2001). Switching and signaling at the telomere. Cell 106: 661–673.

  9. Blackburn EH . (2005). Cell biology: shaggy mouse tales. Nature 486: 922–923.

  10. Blackburn EH, Gall JG . (1978). A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. J Mol Biol 120: 33–53.

  11. Blackburn EH, Greider CW, Szostak JW . (2006). Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med 12: 1133–1138.

  12. Blasco MA . (2005). Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 6: 611–622.

  13. Blasco MA . (2007). The epigenetic regulation of mammalian telomeres. Nat Rev Genet 8: 299–309.

  14. Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA et al. (1997). Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91: 25–34.

  15. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB et al. (1998). Extension of life-span by introduction of telomerase into normal human cells. Science 279: 349–352.

  16. Bryan TM, Reddel RR . (1997). Telomere dynamics and telomerase activity in in vitro immortalised human cells. Eur J Cancer 33: 767–773.

  17. Canela A, Martin-Caballero J, Flores JM, Blasco MA . (2004). Constitutive expression of Tert in thymocytes leads to increased incidence and dissemination of T-cell lymphoma in Lck-Tert mice. Mol Cell Biol 24: 4275–4293.

  18. Cavalier-Smith T . (1974). Palindromic base sequences and replication of eukaryote chromosome ends. Nature 250: 467–470.

  19. Chan SR, Blackburn EH . (2004). Telomeres and telomerase. Trans R Soc Land Biol Sci 359: 109–121.

  20. Choudhury AR, Ju Z, Djojosubroto MW, Schienke A, Lechel A, Schaetzlein S et al. (2007). Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet 39: 99–105.

  21. Collins K, Mitchell JR . (2002). Telomerase in the human organism. Oncogene 21: 564–579.

  22. Cooper JP, Nimmo ER, Allshire RC, Cech TR . (1997). Regulation of telomere length and function by a Myb-domain protein in fission yeast. Nature 385: 744–747.

  23. Counter CM, Hirte HW, Bacchetti S, Harley CB . (1994). Telomerase activity in human ovarian carcinoma. Proc Natl Acad Sci USA 91: 2900–2904.

  24. Dancis BM, Holmquist GP . (1979). Telomere replication and fusion in eukaryotes. J Theor Biol 78: 211–224.

  25. De Lange T . (2005). Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19: 2100–2110.

  26. Dunn B, Szauter P, Pardue ML, Szostak JW . (1984). Transfer of yeast telomeres to linear plasmids by recombination. Cell 39: 191–201.

  27. Espejel S, Klatt P, Ménissier-de Murcia J, Martín-Caballero J, Flores JM, Taccioli G et al. (2004). Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86 or DNA-PKcs. J Cell Biol 167: 627–638.

  28. Flores I, Benetti R, Blasco MA . (2006). Telomerase regulation and stem cell behaviour. Curr Opin Cell Biol 18: 254–260.

  29. Flores I, Cayuela ML, Blasco MA . (2005). Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309: 1253–1256.

  30. Garcia-Cao M, O'Sullivan R, Peters AH, Jenuwein T, Blasco MA . (2004). Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat Genet 36: 94–99.

  31. González-Suárez E, Geserick C, Flores JM, Blasco MA . (2005). Antagonistic effects of telomerase on cancer and aging in K5-mTert transgenic mice. Oncogene 24: 2256–2270.

  32. González-Suárez E, Samper E, Flores JM, Blasco MA . (2000). Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nat Genet 26: 114–117.

  33. González-Suárez E, Samper E, Ramírez A, Flores JM, Martín-Caballero J, Jorcano JL et al. (2001). Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J 20: 2619–2630.

  34. Gonzalo S, Jaco I, Fraga MF, Chen T, Li E, Esteller M et al. (2006). DNA methytransferases control telomere length and telomere recombination in mammalian cells. Nat Cell Biol 8: 416–424.

  35. Gottschling DE, Aparicio CM, Billington BL, Zakian VA . (1990). Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell 16: 751–762.

  36. Greenberg RA, Chin L, Femino A, Lee KH, Gottlieb GJ, Singer RH et al. (1999). Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse. Cell 97: 515–525.

  37. Greider CW, Blackburn EH . (1985). Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43: 405–413.

  38. Greider CW, Blackburn EH . (1987). The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity. Cell 51: 887–898.

  39. Greider CW, Blackburn EH . (1989). A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337: 331–337.

  40. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H et al. (1999). Mammalian telomeres end in a large duplex loop. Cell 97: 503–514.

  41. Hackett JA, Feldser DM, Greider CW . (2001). Telomere dysfunction increases mutationrate and genomic instability. Cell 108: 275–286.

  42. Hackett JA, Greider CW . (2002). Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis. Oncogene 21: 619–626.

  43. Hande MP, Samper E, Lansdorp P, Blasco MA . (1999). Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. J Cell Biol 22: 589–601.

  44. Hao LY, Armanios M, Strong MA, Karim B, Feldser DM, Huso D et al. (2005). Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 16: 1121–1131.

  45. Harley CB . (2008). Telomerase and cancer therapeutics. Nat Rev Cancer 8: 167–179.

  46. Harley CB, Futcher AB, Greider CW . (1990). Telomeres shorten during ageing of human fibroblasts. Nature 345: 458–460.

  47. Hayflick L . (1998). A brief history of the mortality and immortality of cultured cells. Keio J Med 47: 174–182.

  48. Hayflick L, Moorhead PS . (1961). The serial cultivation of human diploid cell strains. Exp Cell Res 25: 585–621.

  49. Hermann 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: 67–77.

  50. Herrera E, Martínez AC, Blasco MA . (2000). Impaired germinal center formation in telomerase-deficient mice. EMBO J 19: 472–481.

  51. Herrera E, Samper E, Martín-Caballero J, Flores JM, Lee HW, Blasco MA . (1999). Disease states associated to telomerase deficiency appear earlier in mice with short telomeres. EMBO J 18: 2950–2960.

  52. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL et al. (1994). Specific association of human telomerase activity with immortal cells and cancer. Science 266: 2011–2015.

  53. Kolquist KA, Ellisen LW, Counter CM, Meyerson M, Tan LK, Weinberg RA et al. (1998). Expression of TERT in early premalignant lesions and a subset of cells in normal tissues. Nat Genet 19: 182–186.

  54. Lee HW, Blasco MA, Gottlieb GJ, Greider CW, DePinho RA . (1998). Essential role of mouse telomerase in highly proliferative organs. Nature 392: 569–574.

  55. Li S, Crothers J, Hagg CM, Blackburn EH . (2005). Cellular and gene expression responses involved in the rapid growth inhibition of human cancer cells by RNA interference-mediated depletion of telomerase RNA. J Biol Chem 280: 23709–23717.

  56. Luke B, Lingner J . (2009). TERRA: telomeric repeat-containing RNA. EMBO J 28: 2503–2510.

  57. Lundblad V, Szostak JW . (1989). A mutant with a defect in telomere elongation leads to senescence in yeast. Cell 57: 633–643.

  58. Mason PJ, Wilson D, Bessler M . (2005). Dyskeratosis congenita—a disease of dysfunctional telomere maintenance. Curr Mol Med 5: 159–170.

  59. McClintock B . (1939). The behavior in successive nuclear divisions of a chromosome broken at meiosis. Proc Natl Acad Sci USA 25: 405–416.

  60. McClintock B . (1941). The stability of broken ends of chromosomes in Zea Mays. Genetics 28: 234–282.

  61. McKay JD, Hung RJ, Gaborieau V, Boffetta P, Chabrier A, Byrnes G et al. (2008). Lung cancer susceptibility locus at 5p15.33. Nat Genet 40: 1404–1406.

  62. Mitchell JR, Wood E, Collins K . (1999). A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402: 551–555.

  63. Morrish TA, Greider CW . (2009). Short telomeres initiate telomere recombination in primary and tumor cells. PLoS Genet 5: e1000357.

  64. Müller HJ . (1938). Bar duplication. Collecting Net (Woods Hole) 13: 181–198.

  65. Olovnikov AM . (1971). Principle of marginotomy in template synthesis of polynucleotides. Dokl Akad Nauk SSSR 201: 1496–1499.

  66. 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: 181–190.

  67. Palladino F, Laroche T, Gilson E, Axelrod A, Philus L, Gasser SM . (1993). SIR3 and SIR4 proteins are required for the positioning and integrity of yeast telomeres. Cell 75: 543–555.

  68. Pardue ML, DeBaryshe PG . (2003). Retrotransposons provide an evolutionarily robust non-telomerase mechanism to maintain telomeres. Annu Rev Genet 37: 485–511.

  69. Rafnar T, Sulen P, Stacey SN, Geller F, Gudmundsson J, Sigurdsson A et al. (2009). Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nat Genet 41: 221–227.

  70. Samper E, Goytisolo FA, Menissier-de Murcia J, González-Suárez E, Cigudosa JC, de Murcia G et al. (2001). Normal telomere length and chromosomal end-capping in poly (ADP-ribose) polymerase deficient mice and primary cells despite increased chromosomal instability. J Cell Biol 154: 49–60.

  71. Sarin KY, Cheung P, Gilson D, Lee E, Tennen RL, Wang E et al. (2005). Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 436: 1048–1052.

  72. Schoeftner S, Blasco MA . (2008). Developmentally regulated transcription of mamalian telomeres by DNA dependent RNA polymerase II. Nat Cell Biol 10: 228–236.

  73. Schoeftner S, Blasco MA . (2009a). A higher order of telomere regulation: telomere heterochromatin and telomeric RNAs. EMBO J 28: 2323–2336.

  74. Schoeftner S, Blasco MA . (2009b). Chromatin regulation and non-coding RNAs at mammalian telomeres. Semin Cell Dev Biol. (e-pub ahead of print).

  75. Shampay J, Szostak JW, Blackburn EH . (1984). DNA sequences of telomeres maintained in yeast. Nature 310: 154–157.

  76. Shete S, Hosking FJ, Robertson LB, Dobbins SE, Sanson M, Malmer B et al. (2009). Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet 4: 899–904.

  77. Siegl-Cachedenier I, Muñoz P, Flores JM, Klatt P, Blasco MA . (2007). Deficient mismatch repair improves organismal fitness and survival of mice with dysfunctional telomeres. Genes Dev 21: 2234–2247.

  78. Stacey SN, Sulem P, Masson G, Bergthorsson JT, Kumar R, Thorleifsson G et al. (2009). Common variants on 1p36 and 1q42 are associated with cutaneous basal cell carcinoma but not with melanoma or pigmentation traits. Nat Genet 41: 809–814.

  79. Szostak JW, Blackburn EH . (1982). Cloning yeast telomeres on linear plasmid vectors. Cell 29: 245–255.

  80. Tomás-Loba A, Flores I, Fernández-Marcos PJ, Cayuela ML, Maraver A, Tejera A et al. (2009). Telomerase reverse transcriptase delays aging in cancer resistant mice. Cell 135: 609–622.

  81. Vera E, Canela A, Fraga MF, Esteller M, Blasco MA . (2008). Epigenetic regulation of telomeres in human cancer. Oncogene 27: 8817–8833.

  82. Watson JD . (1972). Origin of concatemeric T7 DNA. Nat New Biol 239: 197–201.

  83. Wong KK, Maser RS, Bachoo RM, Menon J, Carrasco DR, Gu Y et al. (2003). Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421: 643–648.

Download references

Author information

Correspondence to M A Blasco.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Varela, E., Blasco, M. 2009 Nobel Prize in Physiology or Medicine: telomeres and telomerase. Oncogene 29, 1561–1565 (2010). https://doi.org/10.1038/onc.2010.15

Download citation

Further reading