The epigenetic regulation of mammalian telomeres (original) (raw)
de Lange, T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev.19, 2100–2110 (2005). A must-read review on the protein composition of mammalian telomeres and their role in the regulation of telomere length and telomere capping. ArticleCASPubMed Google Scholar
Chan, S. W. & Blackburn, E. H. New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin. Oncogene21, 553–563 (2002). ArticleCASPubMed Google Scholar
Liu, D., O'Connor, M. S., Qin, J. & Songyang, Z. Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J. Biol. Chem.279, 51338–51342 (2004). ArticleCASPubMed Google Scholar
Muntoni, A. & Reddel, R. R. The first molecular details of ALT in human tumor cells. Hum. Mol. Genet.14, 191–196 (2005). Article Google Scholar
Dunham, M. A., Neumann, A. A., Fasching, C. L. & Reddel, R. R. Telomere maintenance by recombination in human cells. Nature Genet.26, 447–450 (2000). ArticleCASPubMed Google Scholar
Slagboom, P. E., Droog, S. & Boomsma, D. I. Genetic determination of telomere size in humans: a twin study of three age groups. Am. J. Hum. Genet.55, 876–882 (1994). CASPubMedPubMed Central Google Scholar
Zhu, L. et al. Telomere length regulation in mice is linked to a novel chromosome locus. Proc. Natl Acad. Sci. USA95, 8648–8653 (1998). ArticleCASPubMedPubMed Central Google Scholar
Flores, I., Cayuela, M. L. & Blasco, M. A. Effects of telomerase and telomere length on epidermal stem cell behavior. Science309, 1253–1256 (2005). ArticleCASPubMed Google Scholar
Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell91, 25–34 (1997). ArticleCASPubMed Google Scholar
Lee, H.-W., Blasco, M. A., Gottlieb, G. J., Greider, C. W. & DePinho, R. A. Essential role of mouse telomerase in highly proliferative organs. Nature392, 569–574 (1998). ArticleCASPubMed Google Scholar
Herrera, E. et al. Disease states associated to telomerase deficiency appear earlier in mice with short telomeres. EMBO J.18, 2950–2960 (1999). ArticleCASPubMedPubMed Central Google Scholar
Mason, P. J., Wilson, D. B. & Bessler, M. Dyskeratosis congenita — a disease of dysfunctional telomere maintenance. Curr. Mol. Med.5, 159–170 (2005). ArticleCASPubMed Google Scholar
Shay, J. W. & Wright, W. E. Telomerase therapeutics for cancer: challenges and new directions. Nature Rev. Drug Discov.5, 577–584 (2006). ArticleCAS Google Scholar
Baur, J. A., Zou, Y., Shay, J. W. & Wright, W. E. Telomere position effect in human cells. Science292, 2075 (2001). ArticleCASPubMed Google Scholar
Koering, C. E. et al. Human telomeric position effect is determined by chromosomal context and telomeric chromatin integrity. EMBO Rep.3, 1055–1061 (2002). References 15 and 16 provide conclusive evidence that TPE (or 'silencing' of genes near the telomeres) operates in mammalian cells. ArticleCASPubMedPubMed Central Google Scholar
Makarov, V. L., Lejnine, S., Bedoyan, J. & Langmore, J. P. Nucleosomal organization of telomere-specific chromatin in rat. Cell73, 775–787 (1993). ArticleCASPubMed Google Scholar
Garcia-Cao, M., O'Sullivan, R., Peters, A. H., Jenuwein, T. & Blasco, M. A. Epigenetic regulation of telomere length in mammalian cells by the SUV39H1 and SUV39H2 histone methyltransferases. Nature Genet.36, 94–99 (2004). ArticleCASPubMed Google Scholar
Gonzalo, S. et al. Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nature Cell Biol.7, 420–428 (2005). ArticleCASPubMed Google Scholar
Gonzalo, S. et al. DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nature Cell Biol.8, 416–424 (2006). This work shows that mammalian subtelomeric DNA is heavily methylated, and that this epigenetic modification acts as a negative regulator of telomere length and telomere recombination independently of histone methylation. ArticleCASPubMed Google Scholar
Fraga, M. F. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature Genet.37, 391–400 (2005). ArticleCASPubMed Google Scholar
van Overveld, P. G. et al. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nature Genet.35, 315–317 (2003). ArticleCASPubMed Google Scholar
Garcia-Cao, M., Gonzalo, S., Dean, D. & Blasco, M. A. A role for the Rb family of proteins in controlling telomere length. Nature Genet.32, 415–419 (2002). ArticleCASPubMed Google Scholar
Blasco, M. A. Telomeres and human disease: ageing, cancer and beyond. Nature Rev. Genet.6, 611–622 (2005). ArticleCASPubMed Google Scholar
Griffith, J. D. et al. Mammalian telomeres end in a large duplex loop. Cell97, 503–514 (1999). ArticleCASPubMed Google Scholar
de Lange, T. T-loops and the origin of telomeres. Nature Rev. Mol. Cell Biol.5, 323–329 (2004). ArticleCAS Google Scholar
Conrad, M. N., Wright, J. H., Wolf, A. J. & Zakian, V. A. Rap1 protein interacts with yeast telomeres in vivo: overproduction alters telomere structure and decreases chromosome stability. Cell63, 739–750 (1990). ArticleCASPubMed Google Scholar
Nugent, C. I., Hughes, T. R., Lue, N. F. & Lundblad, V. Cdc13p: a single-strand telomeric DNA-binding protein with a dual role in yeast telomere maintenance. Science274, 249–252 (1996). ArticleCASPubMed Google Scholar
Tham, W. H. & Zakian, V. A. Transcriptional silencing at Saccharomyces telomeres: implications for other organisms. Oncogene21, 512–521 (2002). A must-read review on budding yeast telomeric heterochromatin and its roles in controlling telomere length and telomeric silencing. ArticleCASPubMed Google Scholar
Marcand, S., Gilson, E. & Shore, D. A protein-counting mechanism for telomere length regulation in yeast. Science275, 986–990 (1997). ArticleCASPubMed Google Scholar
Kyrion, G., Boakye, K. A. & Lustig, A. J. C-terminal truncation of RAP1 results in the deregulation of telomere size, stability, and function in Saccharomyces cerevisiae. Mol. Cell. Biol.12, 5159–5173 (1992). ArticleCASPubMedPubMed Central Google Scholar
Krauskopf, A. & Blackburn, E. H. Control of telomere growth by interactions of RAP1 with the most distal telomeric repeats. Nature383, 354–357 (1996). ArticleCASPubMed Google Scholar
Levy, D. L. & Blackburn, E. H. Counting of Rif1p and Rif2p on Saccharomyces cerevisiae telomeres regulates telomere length. Mol. Cell. Biol.24, 10857–10867 (2004). ArticleCASPubMedPubMed Central Google Scholar
Palladino, F. et al. SIR3 and SIR4 proteins are required for the positioning and integrity of yeast telomeres. Cell75, 543–555 (1993). ArticleCASPubMed Google Scholar
Cooper, J. P., Nimmo, E. R., Allshire, R. C. & Cech, T. R. Regulation of telomere length and function by a MYB-domain protein in fission yeast. Nature385, 744–747 (1997). ArticleCASPubMed Google Scholar
Baumann, P. & Cech, T. R. POT1, the putative telomere end-binding protein in fission yeast and humans. Science292, 1171–1175 (2001). ArticleCASPubMed Google Scholar
Kanoh, J. & Ishikawa, F. spRap1 and spRif1, recruited to telomeres by Taz1, are essential for telomere function in fission yeast. Curr. Biol.11, 1624–1630 (2001). ArticleCASPubMed Google Scholar
Ye, J. Z. et al. POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev.18, 1649–1654 (2004). ArticleCASPubMedPubMed Central Google Scholar
Liu, D. et al. PTOP interacts with POT1 and regulates its localization to telomeres. Nature Cell Biol.6, 673–680 (2004). ArticleCASPubMed Google Scholar
Smith, S., Giriat, I., Schmitt, A. & de Lange, T. Tankyrase, a poly(ADP-ribose) polymerase at human telomeres. Science282, 1484–1487 (1998). ArticleCASPubMed Google Scholar
Celli, G. B. & de Lange, T. DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion. Nature Cell Biol.7, 712–718 (2005). ArticleCASPubMed Google Scholar
Hockemeyer, D., Daniela, J. P., Takai, H. & de Lange, T. Recent expansion of the telomeric complex in rodents: two distinct POT1 proteins protect mouse telomeres. Cell126, 63–77 (2006). ArticleCASPubMed Google Scholar
Zhu, X. D., Kuster, B., Mann, M., Petrini, J. H. & Lange, T. Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nature Genet.25, 347–352 (2000). ArticleCASPubMed Google Scholar
Samper, E., Goytisolo, F. A., Slijepcevic, P., van Buul, P. P. & Blasco, M. A. Mammalian KU86 protein prevents telomeric fusions independently of the length of TTAGGG repeats and the G-strand overhang. EMBO Rep.1, 244–252 (2000). ArticleCASPubMedPubMed Central Google Scholar
Tarsounas, M. et al. Telomere maintenance requires the RAD51D recombination/repair protein. Cell117, 337–347 (2004). ArticleCASPubMed Google Scholar
Karlseder, J. et al. The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response. PLoS Biol.2, e240 (2004). ArticleCASPubMedPubMed Central Google Scholar
Bradshaw, P. S., Stavropoulos, D. J & Meyn, M. S. Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage. Nature Genet.37, 193–197 (2005). ArticleCASPubMed Google Scholar
Oh, B.-K., Kim, Y.-J., Park, C. & Park, Y. N. Up-regulation of telomere-binding proteins, TRF1, TRF2, and TIN2 is related to telomere shortening during human multistep hepatocarcinogenesis. Am. J. Pathol.166, 73–80 (2005). ArticleCASPubMedPubMed Central Google Scholar
Matsutani, N. et al. Expression of telomeric repeat binding factor 1 and 2 and TRF1-interacting nuclear protein 2 in human gastric carcinomas. Int. J. Oncol.19, 507–512 (2001). CASPubMed Google Scholar
Muñoz, P. et al. XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer. Nature Genet.10, 1063 (2005). ArticleCAS Google Scholar
Nakanishi, K. et al. Expression of mRNAs for telomeric repeat binding factor (TRF)-1 and TRF2 in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Clin. Cancer Res.9, 1105–1111 (2003). CASPubMed Google Scholar
Bellon, M. et al. Increased expression of telomere length regulating factors TRF1, TRF2 and TIN2 in patients with adult T-cell leukemia. Int. J. Cancer119, 2090–2097 (2006). ArticleCASPubMed Google Scholar
Blanco, R., Muñ oz, P., Klatt, P., Flores, J. M. & Blasco, M. A. Telomerase abrogation dramatically accelerates TRF2-induced epithelial carcinogenesis. Genes Dev.21, 206–220 (2007). ArticleCASPubMedPubMed Central Google Scholar
Lazzerini Denchi, E., Celli, G. & de Lange, T. Hepatocytes with extensive telomere deprotection and fusion remain viable and regenerate liver mass through endoreduplication. Genes Dev.20, 2648–2653 (2006). ArticleCASPubMedPubMed Central Google Scholar
Flores, I., Cayuela, M. L. & Blasco, M. A. Effects of telomerase and telomere length on epidermal stem cell behavior. Science309, 1253–1256 (2005). ArticleCASPubMed Google Scholar
Mason, J. M. & Biessmann, H. The unusual telomeres of Drosophila. Trends Genet.11, 58–62 (1995). ArticleCASPubMed Google Scholar
Lundblad, V. & Blackburn, E. H. An alternative pathway for yeast telomere maintenance rescues _est1_- senescence. Cell73, 347–360 (1993). ArticleCASPubMed Google Scholar
Le, S., Moore, J. K., Haber, J. E. & Greider, C. W. RAD50 and RAD51 define two pathways that collaborate to maintain telomeres in the absence of telomerase. Genetics152, 143–152 (1999). CASPubMedPubMed Central Google Scholar
Teng, S. C. & Zakian, V. A. Telomere–telomere recombination is an efficient bypass pathway for telomere maintenance in Saccharomyces cerevisiae. Mol. Cell. Biol.19, 8083–8093 (1999). ArticleCASPubMedPubMed Central Google Scholar
Hande, M. P., Samper, E., Lansdorp, P. & Blasco, M. A. Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. J. Cell Biol.44, 589–601 (1999). Article Google Scholar
Chang, S., Khoo, C. M., Naylor, M. L., Maser, R. S. & DePinho, R. A. Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression. Genes Dev.17, 88–100 (2003). ArticleCASPubMedPubMed Central Google Scholar
Niida, H. et al. Telomere maintenance in telomerase-deficient mouse embryonic stem cells: characterization of an amplified telomeric DNA. Mol. Cell. Biol.20, 4115–4127 (2000). ArticleCASPubMedPubMed Central Google Scholar
Herrera, E., Martinez, A. C. & Blasco, M. A. Impaired germinal center reaction in mice with short telomeres. EMBO J.19, 472–481 (2000). ArticleCASPubMedPubMed Central Google Scholar
Laud, P. R. et al. Elevated telomere–telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway. Genes Dev.19, 2560–2570 (2005). ArticleCASPubMedPubMed Central Google Scholar
Wu, L. et al. Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres. Cell126, 49–62 (2006). ArticleCASPubMed Google Scholar
Levis, R., Hazelrigg, T. & Rubin, G. M. Effects of genomic position on the expression of transduced copies of the white gene of Drosophila. Science229, 558–561 (1985). ArticleCASPubMed Google Scholar
Gottschling, D. E., Aparicio, O. M., Billington, B. L. & Zakian, V. A. Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell63, 751–762 (1990). ArticleCASPubMed Google Scholar
Nimmo, E. R., Cranston, G. & Allshire, R. C. Telomere-associated chromosome breakage in fission yeast results in variegated expression of adjacent genes. EMBO J.13, 3801–3811 (1994). ArticleCASPubMedPubMed Central Google Scholar
Kyrion, G., Liu, K., Liu, C. & Lustig, A. J. RAP1 and telomere structure regulate telomere position effects in Saccharomyces cerevisiae. Genes Dev.7, 1146–1159 (1993). ArticleCASPubMed Google Scholar
Aparicio, O. M., Billington, B. L. & Gottschling, D. E. Modifiers of position effect are shared between telomeric and silent mating-type loci in S. cerevisiae. Cell66, 1279–1287 (1991). ArticleCASPubMed Google Scholar
Hecht, A., Laroche, T., Strahl-Bolsinger, S., Gasser, S. M. & Grunstein, M. Histone H3 and H4 N-termini interact with Sir3 and Sir4 proteins: a molecular model for the formation of heterochromatin in yeast. Cell80, 583–592 (1995). A molecular model for how heterochromatin is formed at budding yeast telomeres is first proposed here. ArticleCASPubMed Google Scholar
Moretti, P. & Shore, D. Multiple interactions in Sir protein recruitment by Rap1p at silencers and telomeres in yeast. Mol. Cell. Biol.21, 8082–8094 (2001). ArticleCASPubMedPubMed Central Google Scholar
Wright, J. H., Gottschling, D. E. & Zakian, V. A. Saccharomyces telomeres assume a non-nucleosomal chromatin structure. Genes Dev.6, 197–210 (1992). ArticleCASPubMed Google Scholar
Luo, K., Vega-Palas, M. A. & Grunstein, M. Rap1–Sir4 binding independent of other Sir, yKu, or histone interactions initiates the assembly of telomeric heterochromatin in yeast. Genes Dev.16, 1528–1539 (2002). ArticleCASPubMedPubMed Central Google Scholar
Strahl-Bolsinger, S., Hecht, A., Luo, K. & Grunstein, M. SIR2 and SIR4 interactions differ in core and extended telomeric heterochromatin in yeast. Genes Dev.11, 83–93 (1997). ArticleCASPubMed Google Scholar
de Bruin, D., Kantrow, S. M., Liberatore, R. A. & Zakian, V. A. Telomere folding is required for the stable maintenance of telomere position effects in yeast. Mol. Cell. Biol.20, 7991–8000 (2000). ArticleCASPubMedPubMed Central Google Scholar
Maillet, L. et al. Evidence for silencing compartments within the yeast nucleus: a role for telomere proximity and Sir protein concentration in silencer-mediated repression. Genes Dev.10, 1796–1811 (1996). ArticleCASPubMed Google Scholar
Fourel, G., Revardel, E., Koering, C. E. & Gilson, E. Cohabitation of insulators and silencing elements in yeast subtelomeric regions. EMBO J.18, 2522–2537 (1999). ArticleCASPubMedPubMed Central Google Scholar
Emre, N. C. et al. Maintenance of low histone ubiquitylation by Ubp10 correlates with telomere-proximal Sir2 association and gene silencing. Mol. Cell17, 585–594 (2005). ArticleCASPubMed Google Scholar
Cenci, G. et al. UbcD1, a Drosophila ubiquitin-conjugating enzyme required for proper telomere behavior. Genes Dev.11, 863–875 (1997). ArticleCASPubMed Google Scholar
Greenwell, P. W. et al. TEL1, a gene involved in controlling telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene. Cell82, 823–829 (1995). ArticleCASPubMed Google Scholar
Porter, S. E., Greenwell, P. W., Ritchie, K. B. & Petes, T. D. The DNA-binding protein Hdf1p (a putative Ku homologue) is required for maintaining normal telomere length in Saccharomyces cerevisiae. Nucleic Acids Res.24, 582–585 (1996). ArticleCASPubMedPubMed Central Google Scholar
Nislow, C., Ray, E. & Pillus, L. SET1, a yeast member of the trithorax family, functions in transcriptional silencing and diverse cellular processes. Mol. Biol. Cell8, 2421–2436 (1997). ArticleCASPubMedPubMed Central Google Scholar
Gartenberg, M. R., Neumann, F. R., Laroche, T., Blaszczyk, M. & Gasser, S. M. Sir-mediated repression can occur independently of chromosomal and subnuclear contexts. Cell119, 955–967 (2004). ArticleCASPubMed Google Scholar
Hediger, F., Berthiau, A. S., van Houwe, G., Gilson, E. & Gasser, S. M. Subtelomeric factors antagonize telomere anchoring and Tel1-independent telomere length regulation. EMBO J.25, 857–867 (2006). ArticleCASPubMedPubMed Central Google Scholar
Teng, S. C., Chang, J., McCowan, B. & Zakian, V. A. Telomerase-independent lengthening of yeast telomeres occurs by an abrupt Rad50p-dependent, Rif-inhibited recombinational process. Mol. Cell6, 947–952 (2000). ArticleCASPubMed Google Scholar
Nakayama, J., Rice, J. C., Strahl, B. D., Allis, C. D. & Grewal, S. I. Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science292, 110–113 (2001). ArticleCASPubMed Google Scholar
Volpe, T. A. et al. Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science297, 1833–1837 (2002). ArticleCASPubMed Google Scholar
Kanoh, J., Sadaie, M., Urano, T. & Ishikawa, F. Telomere binding protein Taz1 establishes Swi6 heterochromatin independently of RNAi at telomeres. Curr. Biol.15, 1808–1819 (2005). ArticleCASPubMed Google Scholar
Ueno, M. et al. Fission yeast Arp6 is required for telomere silencing, but functions independently of Swi6. Nucleic Acids Res.32, 736–741 (2004). ArticleCASPubMedPubMed Central Google Scholar
Ekwall, K. et al. Mutations in the fission yeast silencing factors clr4+ and rik1+ disrupt the localisation of the chromo domain protein Swi6p and impair centromere function. J. Cell Sci.109, 2637–2648 (1996). CASPubMed Google Scholar
Hall, I. M., Noma, K. & Grewal, S. I. RNA interference machinery regulates chromosome dynamics during mitosis and meiosis in fission yeast. Proc. Natl Acad. Sci. USA100, 193–198 (2003). ArticleCASPubMed Google Scholar
Perrini, B. et al. HP1 controls telomere capping, telomere elongation, and telomere silencing by two different mechanisms in Drosophila. Mol. Cell15, 467–476 (2004). ArticleCASPubMed Google Scholar
Savitsky, M., Kwon, D., Georgiev, P., Kalmykova, A. & Gvozdev, V. Telomere elongation is under the control of the RNAi-based mechanism in the Drosophila germline. Genes Dev.20, 345–354 (2006). ArticleCASPubMedPubMed Central Google Scholar
Xhemalce, B., Seeler, J. S., Thon, G., Dejean, A. & Arcangioli, B. Role of the fission yeast SUMO E3 ligase Pli1p in centromere and telomere maintenance. EMBO J.23, 3844–3853 (2004). ArticleCASPubMedPubMed Central Google Scholar
Xhemalce, B. et al. Role of SUMO in the dynamics of telomere maintenance in fission yeast. Proc. Natl Acad. Sci. USA.104, 893–898 (2007). A role for SUMO proteins in telomerase-mediated telomere elongation is first shown here. ArticleCASPubMedPubMed Central Google Scholar
Kanoh, J. et al. The fission yeast spSet1p is a histone H3-K4 methyltransferase that functions in telomere maintenance and DNA repair in an ATM kinase Rad3-dependent pathway. J. Mol. Biol.326, 1081–1094 (2003). ArticleCASPubMed Google Scholar
Peters, A. H. et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell107, 323–337 (2001). ArticleCASPubMed Google Scholar
Schotta, G. et al. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev18, 1251–1262 (2004). ArticleCASPubMedPubMed Central Google Scholar
Kourmouli, N. et al. Heterochromatin and tri-methylated lysine 20 of histone 4 in mammals. J. Cell Sci.117, 2491–2501 (2004). ArticleCASPubMed Google Scholar
Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature410, 116–120 (2001). ArticleCASPubMed Google Scholar
Benetti, R., Garcia-Cao, M. & Blasco, M. A. Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres. Nature Genet.39, 243–250 (2007). Shows for the first time that telomere shortening to a critical length in mammals results in loss of histone and DNA methylation at mammalian telomeres and subtelomeres, concomitant with increased histone acetylation. ArticleCASPubMed Google Scholar
Netzer, C. et al. SALL1, the gene mutated in Townes–Brocks syndrome, encodes a transcriptional repressor which interacts with TRF1/PIN2 and localizes to pericentromeric heterochromatin. Hum. Mol. Genet.10, 3017–3024 (2001). ArticleCASPubMed Google Scholar
Kaminker, P. et al. Higher-order nuclear organization in growth arrest of human mammary epithelial cells: a novel role for telomere-associated protein TIN2. J Cell Sci.118, 1321–1330 (2005). ArticleCASPubMed Google Scholar
Jones, P. A. & Baylin, S. B. The fundamental role of epigenetic events in cancer. Nature Rev. Genet.3, 415–428 (2002). ArticleCASPubMed Google Scholar
Dominguez-Bendala, J. & McWhir, J. Enhanced gene targeting frequency in ES cells with low genomic methylation levels. Transgenic Res.13, 69–74 (2004). ArticleCASPubMed Google Scholar
Bender, J. Cytosine methylation of repeated sequences in eukaryotes: the role of DNA pairing. Trends Biochem. Sci.23, 252–256 (1998). ArticleCASPubMed Google Scholar
Pedram, M. et al. Telomere position effect and silencing of transgenes near telomeres in the mouse. Mol. Cell. Biol.26, 1865–1878 (2006). ArticleCASPubMedPubMed Central Google Scholar
Okano, M., Bell, D. W., Haber, D. A. & Li, E. DNA methyltransferases DNMT3a and DNMT3b are essential for de novo methylation and mammalian development. Cell99, 247–257 (1999). ArticleCASPubMed Google Scholar
Okano, M., Xie, S. & Li, E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nature Genet.19, 219–220 (1998). ArticleCASPubMed Google Scholar
Chen, T., Tsujimoto, N. & Li, E. The PWWP domain of Dnmt3a and Dnmt3b is required for directing DNA methylation to the major satellite repeats at pericentric heterochromatin. Mol. Cell. Biol.24, 9048–9058 (2004). ArticleCASPubMedPubMed Central Google Scholar
Ofir, R., Wong, A. C., McDermid, H. E., Skorecki, K. L. & Selig, S. Position effect of human telomeric repeats on replication timing. Proc. Natl Acad. Sci. USA96, 11434–11439 (1999). ArticleCASPubMedPubMed Central Google Scholar
Jiang, G. et al. Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q. Hum. Mol. Genet.12, 2909–2921 (2003). ArticleCASPubMed Google Scholar
Bayne, R. A. L. et al. Sandwiching of a gene within 12 kb of a functional telomere and alpha satellite does not result in silencing. Hum Mol Genet.3, 539–546 (1994). ArticleCASPubMed Google Scholar
Wright, W. E., Tesmer, V. M., Liao, M. L., & Shay, J. W. Normal human telomeres are not late replicating. Exp. Cell Res.251, 492–499 (1999). ArticleCASPubMed Google Scholar
Ancelin, K. et al. Targeting assay to study the cis functions of human telomeric proteins: evidence for inhibition of telomerase by TRF1 and for activation of telomere degradation by TRF2. Mol. Cell. Biol.22, 3474–3487 (2002). ArticleCASPubMedPubMed Central Google Scholar
Loayza, D. & De Lange, T. POT1 as a terminal transducer of TRF1 telomere length control. Nature423, 1013–1018 (2003). ArticleCASPubMed Google Scholar
Wang, R. C., Smogorzewska, A. & de Lange, T. Homologous recombination generates T-loop-sized deletions at human telomeres. Cell119, 355–368 (2004). ArticleCASPubMed Google Scholar
Dynek, J. N. & Smith, S. Resolution of sister telomere association is required for progression through mitosis. Science304, 97–100 (2004). ArticleCASPubMed Google Scholar
Buck, S. W. & Shore, D. Action of a RAP1 carboxy-terminal silencing domain reveals an underlying competition between HMR and telomeres in yeast. Genes Dev.9, 370–384 (1995). ArticleCASPubMed Google Scholar
Wiley, E. A. & Zakian, V. A. Extra telomeres, but not internal tracts of telomeric DNA, reduce transcriptional repression at Saccharomyces telomeres. Genetics139, 67–79 (1995). CASPubMedPubMed Central Google Scholar
Marcand, S., Brevet, V. & Gilson, E. Progressive _cis_-inhibition of telomerase upon telomere elongation. EMBO J.18, 3509–3519 (1999). ArticleCASPubMedPubMed Central Google Scholar
Teixeira, M. T., Arneric, M., Sperisen, P. & Lingner, J. Telomere length homeostasis is achieved via a switch between telomerase-extendible and -nonextendible states. Cell117, 323–335 (2004). This work shows that budding yeast telomerase activity preferentially acts on the shortest telomeres. ArticleCASPubMed Google Scholar
Samper, E., Flores, J. M. & Blasco, M. A. Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc−/− mice with short telomeres. EMBO Rep.2, 800–807 (2001). ArticleCASPubMedPubMed Central Google Scholar
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. Cell107, 67–77 (2001). References 131 and 132 show that mammalian telomerase activity preferentially acts on the shortest telomeres. ArticleCASPubMed Google Scholar
Xu, G. L. et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature402, 187–191 (1999). ArticleCASPubMed Google Scholar
Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet.23, 185–188 (1999). ArticleCASPubMed Google Scholar
Cawthon, R. M. et al. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet361, 393–395 (2003). ArticleCASPubMed Google Scholar
Valdes, A. M. et al. Obesity, cigarette smoking, and telomere length in women. Lancet366, 662–664 (2005). ArticleCASPubMed Google Scholar
Haigis, M. C. et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic β-cells. Cell126, 941–954 (2006). ArticleCASPubMed Google Scholar
Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell124, 315–329 (2006). ArticleCASPubMed Google Scholar
Chua, K. F. et al. Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metab.2, 67–76 (2005). ArticleCASPubMed Google Scholar
Roth, W. et al. PIASy-deficient mice display modest defects in IFN and Wnt signaling. J. Immunol.173, 6189–6199 (2004). ArticleCASPubMed Google Scholar
Nacerddine, K. et al. The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice. Dev. Cell.9, 769–779 (2005). ArticleCASPubMed Google Scholar
Marciniak, R. A. et al. A novel telomere structure in a human alternative lengthening of telomeres cell line. Cancer Res.65, 2730–2737 (2005). ArticleCASPubMed Google Scholar