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Mattern, Karin A., Susan J. J. Swiggers, Alex L. Nigg, Bob Löwenberg, Adriaan B. Houtsmuller i J. Mark J. M. Zijlmans. "Dynamics of Protein Binding to Telomeres in Living Cells: Implications for Telomere Structure and Function". Molecular and Cellular Biology 24, nr 12 (15.06.2004): 5587–94. http://dx.doi.org/10.1128/mcb.24.12.5587-5594.2004.
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ABSTRACT Telomeric proteins have an essential role in the regulation of the length of the telomeric DNA tract and in protection against end-to-end chromosome fusion. Telomere organization and how individual proteins are involved in different telomere functions in living cells is largely unknown. By using green fluorescent protein tagging and photobleaching, we investigated in vivo interactions of human telomeric DNA-binding proteins with telomeric DNA. Our results show that telomeric proteins interact with telomeres in a complex dynamic fashion: TRF2, which has a dual role in chromosome end protection and telomere length homeostasis, resides at telomeres in two distinct pools. One fraction (∼73%) has binding dynamics similar to TRF1 (residence time of ∼44 s). Interestingly, the other fraction of TRF2 binds with similar dynamics as the putative end-protecting factor hPOT1 (residence time of ∼11 min). Our data support a dynamic model of telomeres in which chromosome end-protection and telomere length homeostasis are governed by differential binding of telomeric proteins to telomeric DNA.
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Cook, Brandoch D., Jasmin N. Dynek, William Chang, Grigoriy Shostak i Susan Smith. "Role for the Related Poly(ADP-Ribose) Polymerases Tankyrase 1 and 2 at Human Telomeres". Molecular and Cellular Biology 22, nr 1 (1.01.2002): 332–42. http://dx.doi.org/10.1128/mcb.22.1.332-342.2002.
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ABSTRACT Telomere maintenance is essential for the continuous growth of tumor cells. In most human tumors telomeres are maintained by telomerase, a specialized reverse transcriptase. Tankyrase 1, a human telomeric poly(ADP-ribose) polymerase (PARP), positively regulates telomere length through its interaction with TRF1, a telomeric DNA-binding protein. Tankyrase 1 ADP-ribosylates TRF1, inhibiting its binding to telomeric DNA. Overexpression of tankyrase 1 in the nucleus promotes telomere elongation, suggesting that tankyrase 1 regulates access of telomerase to the telomeric complex. The recent identification of a closely related homolog of tankyrase 1, tankyrase 2, opens the possibility for a second PARP at telomeres. We therefore sought to establish the role of tankyrase 1 at telomeres and to determine if tankyrase 2 might have a telomeric function. We show that endogenous tankyrase 1 is a component of the human telomeric complex. We demonstrate that telomere elongation by tankyrase 1 requires the catalytic activity of the PARP domain and does not occur in telomerase-negative primary human cells. To investigate a potential role for tankyrase 2 at telomeres, recombinant tankyrase 2 was subjected to an in vitro PARP assay. Tankyrase 2 poly(ADP-ribosyl)ated itself and TRF1. Overexpression of tankyrase 2 in the nucleus released endogenous TRF1 from telomeres. These findings establish tankyrase 2 as a bona fide PARP, with itself and TRF1 as acceptors of ADP-ribosylation, and suggest the possibility of a role for tankyrase 2 at telomeres.
3
Hsieh, Yi-Ching, Pei-Jung Tu, Ying-Yuan Lee, Chun-Chen Kuo, Yi-Chien Lin, Chi-Fang Wu i Jing-Jer Lin. "The U3 small nucleolar ribonucleoprotein component Imp4p is a telomeric DNA-binding protein". Biochemical Journal 408, nr 3 (28.11.2007): 387–93. http://dx.doi.org/10.1042/bj20070968.
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Imp4p is a component of U3 snoRNP (small nucleolar ribonucleoprotein) involved in the maturation of 18S rRNA. We have shown that Imp4p interacts with Cdc13p, a single-stranded telomere-binding protein involved in telomere maintenance. To understand the role of Imp4p in telomeres, we purified recombinant Imp4p protein and tested its binding activity towards telomeric DNA using electrophoretic mobility-shift assays. Our results showed that Imp4p bound specifically to single-stranded telomeric DNA in vitro. The interaction of Imp4p to telomeres in vivo was also demonstrated by chromatin immunoprecipitation experiments. Significantly, the binding of Imp4p to telomeres was not limited to yeast proteins, since the hImp4 (human Imp4) also bound to vertebrate single-stranded telomeric DNA. Thus we conclude that Imp4p is a novel telomeric DNA-binding protein that, in addition to its role in rRNA processing, might participate in telomere function.
4
Lin, Chih-Yi Gabriela, Anna Christina Näger, Thomas Lunardi, Aleksandra Vančevska, Gérald Lossaint i Joachim Lingner. "The human telomeric proteome during telomere replication". Nucleic Acids Research 49, nr 21 (8.11.2021): 12119–35. http://dx.doi.org/10.1093/nar/gkab1015.
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Abstract Telomere shortening can cause detrimental diseases and contribute to aging. It occurs due to the end replication problem in cells lacking telomerase. Furthermore, recent studies revealed that telomere shortening can be attributed to difficulties of the semi-conservative DNA replication machinery to replicate the bulk of telomeric DNA repeats. To investigate telomere replication in a comprehensive manner, we develop QTIP-iPOND - Quantitative Telomeric chromatin Isolation Protocol followed by isolation of Proteins On Nascent DNA - which enables purification of proteins that associate with telomeres specifically during replication. In addition to the core replisome, we identify a large number of proteins that specifically associate with telomere replication forks. Depletion of several of these proteins induces telomere fragility validating their importance for telomere replication. We also find that at telomere replication forks the single strand telomere binding protein POT1 is depleted, whereas histone H1 is enriched. Our work reveals the dynamic changes of the telomeric proteome during replication, providing a valuable resource of telomere replication proteins. To our knowledge, this is the first study that examines the replisome at a specific region of the genome.
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Douglas, Max E., i John F. X. Diffley. "Budding yeast Rap1, but not telomeric DNA, is inhibitory for multiple stages of DNA replication in vitro". Nucleic Acids Research 49, nr 10 (28.05.2021): 5671–83. http://dx.doi.org/10.1093/nar/gkab416.
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Abstract Telomeres are copied and reassembled each cell division cycle through a multistep process called telomere replication. Most telomeric DNA is duplicated semiconservatively during this process, but replication forks frequently pause or stall at telomeres in yeast, mouse and human cells, potentially causing chronic telomere shortening or loss in a single cell cycle. We have investigated the cause of this effect by examining the replication of telomeric templates in vitro. Using a reconstituted assay for eukaryotic DNA replication in which a complete eukaryotic replisome is assembled and activated with purified proteins, we show that budding yeast telomeric DNA is efficiently duplicated in vitro unless the telomere binding protein Rap1 is present. Rap1 acts as a roadblock that prevents replisome progression and leading strand synthesis, but also potently inhibits lagging strand telomere replication behind the fork. Both defects can be mitigated by the Pif1 helicase. Our results suggest that GC-rich sequences do not inhibit DNA replication per se, and that in the absence of accessory factors, telomere binding proteins can inhibit multiple, distinct steps in the replication process.
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Higa, Mitsunori, Yukihiro Matsuda, Jumpei Fujii, Nozomi Sugimoto, Kazumasa Yoshida i Masatoshi Fujita. "TRF2-mediated ORC recruitment underlies telomere stability upon DNA replication stress". Nucleic Acids Research 49, nr 21 (11.11.2021): 12234–51. http://dx.doi.org/10.1093/nar/gkab1004.
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Abstract Telomeres are intrinsically difficult-to-replicate region of eukaryotic chromosomes. Telomeric repeat binding factor 2 (TRF2) binds to origin recognition complex (ORC) to facilitate the loading of ORC and the replicative helicase MCM complex onto DNA at telomeres. However, the biological significance of the TRF2–ORC interaction for telomere maintenance remains largely elusive. Here, we employed a TRF2 mutant with mutations in two acidic acid residues (E111A and E112A) that inhibited the TRF2–ORC interaction in human cells. The TRF2 mutant was impaired in ORC recruitment to telomeres and showed increased replication stress-associated telomeric DNA damage and telomere instability. Furthermore, overexpression of an ORC1 fragment (amino acids 244–511), which competitively inhibited the TRF2–ORC interaction, increased telomeric DNA damage under replication stress conditions. Taken together, these findings suggest that TRF2-mediated ORC recruitment contributes to the suppression of telomere instability.
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Yang, Qin, Yun-Ling Zheng i Curtis C. Harris. "POT1 and TRF2 Cooperate To Maintain Telomeric Integrity". Molecular and Cellular Biology 25, nr 3 (1.02.2005): 1070–80. http://dx.doi.org/10.1128/mcb.25.3.1070-1080.2005.
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ABSTRACT Mammalian telomeric DNA contains duplex TTAGGG repeats and single-stranded overhangs. POT1 (protection of telomeres 1) is a telomere-specific single-stranded DNA-binding protein, highly conserved in eukaryotes. The biological function of human POT1 is not well understood. In the present study, we demonstrate that POT1 plays a key role in telomeric end protection. The reduction of POT1 by RNA interference led to the loss of telomeric single-stranded overhangs and induced apoptosis, chromosomal instability, and senescence in cells. POT1 and TRF2 interacted with each other to form a complex with telomeric DNA. A dominant negative TRF2, TRF2ΔBΔM, bound to POT1 and prevented it from binding to telomeres. POT1 overexpression protected against TRF2ΔBΔM-induced loss of telomeric single-stranded overhangs, chromosomal instability, and senescence. These results demonstrate that POT1 and TRF2 share in part in the same pathway for telomere capping and suggest that POT1 binds to the telomeric single-stranded DNA in the D-loop and cooperates with TRF2 in t-loop maintenance.
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Gineitis, Arunas A., Irina A. Zalenskaya, Peter M. Yau, E. Morton Bradbury i Andrei O. Zalensky. "Human Sperm Telomere–Binding Complex Involves Histone H2b and Secures Telomere Membrane Attachment". Journal of Cell Biology 151, nr 7 (25.12.2000): 1591–98. http://dx.doi.org/10.1083/jcb.151.7.1591.
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Telomeres are unique chromatin domains located at the ends of eukaryotic chromosomes. Telomere functions in somatic cells involve complexes between telomere proteins and TTAGGG DNA repeats. During the differentiation of germ-line cells, telomeres undergo significant reorganization most likely required for additional specific functions in meiosis and fertilization. A telomere-binding protein complex from human sperm (hSTBP) has been isolated by detergent treatment and was partially purified. hSTBP specifically binds double-stranded telomeric DNA and does not contain known somatic telomere proteins TRF1, TRF2, and Ku. Surprisingly, the essential component of this complex has been identified as a specific variant of histone H2B. Indirect immunofluorescence shows punctate localization of H2B in sperm nuclei, which in part coincides with telomeric DNA localization established by fluorescent in situ hybridization. Anti–H2B antibodies block interactions of hSTBP with telomere DNA, and spH2B forms specific complex with this DNA in vitro, indicating that this protein plays a role in telomere DNA recognition. We propose that hSTBP participates in the membrane attachment of telomeres that may be important for ordered chromosome withdrawal after fertilization.
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Kelleher, Colleen, Isabel Kurth i Joachim Lingner. "Human Protection of Telomeres 1 (POT1) Is a Negative Regulator of Telomerase Activity In Vitro". Molecular and Cellular Biology 25, nr 2 (15.01.2005): 808–18. http://dx.doi.org/10.1128/mcb.25.2.808-818.2005.
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ABSTRACT The telomeric single-strand DNA binding protein protection of telomeres 1 (POT1) protects telomeres from rapid degradation in Schizosaccharomyces pombe and has been implicated in positive and negative telomere length regulation in humans. Human POT1 appears to interact with telomeres both through direct binding to the 3′ overhanging G-strand DNA and through interaction with the TRF1 duplex telomere DNA binding complex. The influence of POT1 on telomerase activity has not been studied at the molecular level. We show here that POT1 negatively effects telomerase activity in vitro. We find that the DNA binding activity of POT1 is required for telomerase inhibition. Furthermore, POT1 is incapable of inhibiting telomeric repeat addition to substrate primers that are defective for POT1 binding, suggesting that in vivo, POT1 likely affects substrate access to telomerase.
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Groff-Vindman, Cindy, Anthony J. Cesare, Shobhana Natarajan, Jack D. Griffith i Michael J. McEachern. "Recombination at Long Mutant Telomeres Produces Tiny Single- and Double-Stranded Telomeric Circles". Molecular and Cellular Biology 25, nr 11 (1.06.2005): 4406–12. http://dx.doi.org/10.1128/mcb.25.11.4406-4412.2005.
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ABSTRACT Recombinational telomere elongation (RTE) known as alternate lengthening of telomeres is the mechanism of telomere maintenance in up to 5 to 10% of human cancers. The telomeres of yeast mutants lacking telomerase can also be maintained by recombination. Previously, we proposed the roll-and-spread model to explain this elongation in the yeast Kluveromyces lactis. This model suggests that a very small (∼100-bp) circular molecule of telomeric DNA is copied by a rolling circle event to generate a single long telomere. The sequence of this primary elongated telomere is then spread by recombination to all remaining telomeres. Here we show by two-dimensional gel analysis and electron microscopy that small circles of single- and double-stranded telomeric DNA are commonly made by recombination in a K. lactis mutant with long telomeres. These circles were found to be especially abundant between 100 and 400 bp (or nucleotides). Interestingly, the single-stranded circles consist of only the G-rich telomeric strand sequence. To our knowledge this is the first report of single-stranded telomeric circles as a product of telomere dysfunction. We propose that the small telomeric circles form through the resolution of an intratelomeric strand invasion which resembles a t-loop. Our data reported here demonstrate that K. lactis can, in at least some circumstances, make telomeric circles of the very small sizes predicted by the roll-and-spread model. The very small circles seen here are both predicted products of telomere rapid deletion, a process observed in both human and yeast cells, and predicted templates for roll-and-spread RTE.
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Li, Bibo, i Titia de Lange. "Rap1 Affects the Length and Heterogeneity of Human Telomeres". Molecular Biology of the Cell 14, nr 12 (grudzień 2003): 5060–68. http://dx.doi.org/10.1091/mbc.e03-06-0403.
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Telomere length is controlled in part by cis-acting negative regulators that limit telomere extension by telomerase. In budding yeast, the major telomere length regulator scRap1 binds to telomeric DNA and acts to inhibit telomere elongation in cis. Because the human Rap1 ortholog hRap1 does not bind to telomeric DNA directly but is recruited to telomeres by TRF2, we examined its role in telomere length control. The data are consistent with hRap1 being a negative regulator of telomere length, indicating functional conservation. Deletion mapping confirmed that hRap1 is tethered to telomeres through interaction of its C terminus with TRF2. The telomere length phenotypes of hRap1 deletion mutants implicated both the BRCT and Myb domain as protein interaction domains involved in telomere length regulation. By contrast, scRap1 binds to telomeres with its Myb domains and uses its C terminus to recruit the telomere length regulators Rif1 and Rif2. Together, our data show that although the role of Rap1 at telomeres has been largely conserved, the domains of Rap1 have undergone extensive functional changes during eukaryotic evolution. Surprisingly, hRap1 alleles lacking the BRCT domain diminished the heterogeneity of human telomeres, indicating that hRap1 also plays a role in the regulation of telomere length distribution.
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Majerska, Jana, Marianna Feretzaki, Galina Glousker i Joachim Lingner. "Transformation-induced stress at telomeres is counteracted through changes in the telomeric proteome including SAMHD1". Life Science Alliance 1, nr 4 (17.07.2018): e201800121. http://dx.doi.org/10.26508/lsa.201800121.
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Telomeres play crucial roles during tumorigenesis, inducing cellular senescence upon telomere shortening and extensive chromosome instability during telomere crisis. However, it has not been investigated if and how cellular transformation and oncogenic stress alter telomeric chromatin composition and function. Here, we transform human fibroblasts by consecutive transduction with vectors expressing hTERT, the SV40 early region, and activated H-RasV12. Pairwise comparisons of the telomeric proteome during different stages of transformation reveal up-regulation of proteins involved in chromatin remodeling, DNA repair, and replication at chromosome ends. Depletion of several of these proteins induces telomere fragility, indicating their roles in replication of telomeric DNA. Depletion of SAMHD1, which has reported roles in DNA resection and homology-directed repair, leads to telomere breakage events in cells deprived of the shelterin component TRF1. Thus, our analysis identifies factors, which accumulate at telomeres during cellular transformation to promote telomere replication and repair, resisting oncogene-borne telomere replication stress.
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Caslini, Corrado, James A. Connelly, Amparo Serna, Dominique Broccoli i Jay L. Hess. "MLL Associates with Telomeres and Regulates Telomeric Repeat-Containing RNA Transcription". Molecular and Cellular Biology 29, nr 16 (15.06.2009): 4519–26. http://dx.doi.org/10.1128/mcb.00195-09.
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ABSTRACT Mammalian telomeres consist of TTAGGG repeats organized in nucleosomes and associated with a six-protein complex known as shelterin, which preserves telomere structure and protects chromosome ends from the cellular DNA damage response. Recent studies have found that telomeres are transcribed into telomeric UUAGGG repeat-containing RNA (TERRA) starting from subtelomeric regions. TERRA binding at telomeres appears to be involved in cis-based mechanisms of telomeric chromatin organization and maintenance. A number of histone methyltransferases (HMTs) are known to influence telomeric chromatin status; however, the regulatory mechanisms of telomere transcription are poorly understood. Here, we show that the histone 3/lysine 4 (H3/K4) HMT and the transcriptional regulator MLL associate with telomeres and contribute to their H3/K4 methylation and transcription in a telomere length-dependent manner. In human diploid fibroblasts, RNA interference-mediated MLL depletion affects telomere chromatin modification and transcription and induces the telomere damage response. Telomere uncapping through either TRF2 shelterin protein knockdown or exposure to telomere G-strand DNA oligonucleotides significantly increases the transcription of TERRA, an effect mediated by the functional cooperation between MLL and the tumor suppressor p53. In total, our findings identify a previously unrecognized role of MLL in modifying telomeric chromatin and provide evidence for the functional interaction between MLL, p53, and the shelterin complex in the regulation of telomeric transcription and stability.
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Coluzzi, Elisa, Stefano Leone i Antonella Sgura. "Oxidative Stress Induces Telomere Dysfunction and Senescence by Replication Fork Arrest". Cells 8, nr 1 (3.01.2019): 19. http://dx.doi.org/10.3390/cells8010019.
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Oxidative DNA damage, particularly 8-oxoguanine, represents the most frequent DNA damage in human cells, especially at the telomeric level. The presence of oxidative lesions in the DNA can hinder the replication fork and is able to activate the DNA damage response. In this study, we wanted to understand the mechanisms by which oxidative damage causes telomere dysfunction and senescence in human primary fibroblasts. After acute oxidative stress at telomeres, our data demonstrated a reduction in TRF1 and TRF2, which are involved in proper telomere replication and T-loop formation, respectively. Furthermore, we observed a higher level of γH2AX with respect to 53BP1 at telomeres, suggesting a telomeric replication fork stall rather than double-strand breaks. To confirm this finding, we studied the replication of telomeres by Chromosome Orientation-FISH (CO-FISH). The data obtained show an increase in unreplicated telomeres after hydrogen peroxide treatment, corroborating the idea that the presence of 8-oxoG can induce replication fork arrest at telomeres. Lastly, we analyzed the H3K9me3 histone mark after oxidative stress at telomeres, and our results showed an increase of this marker, most likely inducing the heterochromatinization of telomeres. These results suggest that 8-oxoG is fundamental in oxidative stress-induced telomeric damage, principally causing replication fork arrest.
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Esnault, Germain, Stefano Majocchi, Danielle Martinet, Nathalie Besuchet-Schmutz, Jacques S. Beckmann i Nicolas Mermod. "Transcription Factor CTF1 Acts as a Chromatin Domain Boundary That Shields Human Telomeric Genes from Silencing". Molecular and Cellular Biology 29, nr 9 (9.03.2009): 2409–18. http://dx.doi.org/10.1128/mcb.00779-08.
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ABSTRACT Telomeres are associated with chromatin-mediated silencing of genes in their vicinity. However, how epigenetic markers mediate mammalian telomeric silencing and whether specific proteins may counteract this effect are not known. We evaluated the ability of CTF1, a DNA- and histone-binding transcription factor, to prevent transgene silencing at human telomeres. CTF1 was found to protect a gene from silencing when its DNA-binding sites were interposed between the gene and the telomeric extremity, while it did not affect a gene adjacent to the telomere. Protein fusions containing the CTF1 histone-binding domain displayed similar activities, while mutants impaired in their ability to interact with the histone did not. Chromatin immunoprecipitation indicated the propagation of a hypoacetylated histone structure to various extents depending on the telomere. The CTF1 fusion protein was found to recruit the H2A.Z histone variant at the telomeric locus and to restore high histone acetylation levels to the insulated telomeric transgene. Histone lysine trimethylations were also increased on the insulated transgene, indicating that these modifications may mediate expression rather than silencing at human telomeres. Overall, these results indicate that transcription factors can act to delimit chromatin domain boundaries at mammalian telomeres, thereby blocking the propagation of a silent chromatin structure.
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Stock, Amanda, Kun Wang, Chongkui Sun, Chengyu Liu, Yi Gong i Yie Liu. "A DNA Damage Response-Independent Mechanism for Telomere Shortening-Elicited Age-Related Pathologies". Innovation in Aging 4, Supplement_1 (1.12.2020): 885. http://dx.doi.org/10.1093/geroni/igaa057.3268.
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Abstract Telomere attrition is associated with telomeropathies and age-related pathologies. In telomeropathies, telomere uncapping induces a DNA damage response (DDR) that drives apoptosis or senescence. However, a defined mechanism by which telomere attrition contributes to other age-related pathologies has not been determined. Telomere integrity is maintained by shelterin, a six-protein complex. Rap1 is the only shelterin member that is not essential for telomere capping but engages non-telomeric DNA and regulates gene transcription. We hypothesized that non-telomeric Rap1 accumulation could contribute to age-related pathologies in a DDR-independent manner. To test this, we used CRISPR/Cas9 editing to generate a Rap1 mutant mouse model in which Rap1 at telomeres is prevented, leaving only non-telomeric Rap1. Indirect immunostaining showed no differences in telomere dysfunction-induced DDR foci in Rap1 mutant compared to wild-type primary fibroblasts. Cell fractionation/western blotting of fibroblasts from Rap1 mutants demonstrated decreased Rap1 expression and Rap1 re-localization off telomeres, which mimics the same alteration of Rap1 in human cells with telomere attrition. Rap1 mutant mice exhibited increased body weight and altered metabolic and immune-response transcripts in various tissues, indicating that altered transcription could account for some of the observed phenotypes related to telomere attrition. In conclusion, telomere shortening may facilitate non-telomeric Rap1, which alters gene transcription and drives metabolic and immune dysfunction in a DDR-independent manner.
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Stroik, Susanna, Kevin Kurtz i Eric A. Hendrickson. "CtIP is essential for telomere replication". Nucleic Acids Research 47, nr 17 (5.08.2019): 8927–40. http://dx.doi.org/10.1093/nar/gkz652.
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Abstract The maintenance of telomere length is critical to longevity and survival. Specifically, the failure to properly replicate, resect, and/or form appropriate telomeric structures drives telomere shortening and, in turn, genomic instability. The endonuclease CtIP is a DNA repair protein that is well-known to promote genome stability through the resection of endogenous DNA double-stranded breaks. Here, we describe a novel role for CtIP. We show that in the absence of CtIP, human telomeres shorten rapidly to non-viable lengths. This telomere dysfunction results in an accumulation of fusions, breaks, and frank telomere loss. Additionally, CtIP suppresses the generation of circular, extrachromosomal telomeric DNA. These latter structures appear to arise from arrested DNA replication forks that accumulate in the absence of CtIP. Hence, CtIP is required for faithful replication through telomeres via its roles at stalled replication tracts. Our findings demonstrate a new role for CtIP as a protector of human telomere integrity.
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Boccardi, Virginia, Luigi Cari, Giuseppe Nocentini, Carlo Riccardi, Roberta Cecchetti, Carmelinda Ruggiero, Beatrice Arosio, Giuseppe Paolisso, Utz Herbig i Patrizia Mecocci. "Telomeres Increasingly Develop Aberrant Structures in Aging Humans". Journals of Gerontology: Series A 75, nr 2 (2.11.2018): 230–35. http://dx.doi.org/10.1093/gerona/gly257.
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Abstract Telomeres progressively shorten with age, and it has been proposed that critically short and dysfunctional telomeres contribute to aging and aging-associated diseases in humans. For many years it was thought that telomere erosion was strictly a consequence of the “end replication problem,” or the inability of replicative polymerases to completely duplicate linear DNA ends. It is becoming increasingly evident, however, that telomere shortening of cultured human cells is also caused because of other replication defects in telomeric repeats, those that cause fragile telomeres and other aberrant telomeric structures that can be detected on metaphase chromosomes. Whether these replication defects contribute to telomere erosion also in human tissues is currently unknown. By analyzing peripheral blood mononuclear cells from a total of 35 healthy subjects ranging in age from 23 to 101 years, we demonstrated that telomeres increasingly display aberrant structures with advancing donor age. Although the percentages of fragile telomeres increased only until adulthood, the percentages of chromosomes displaying sister telomere loss and sister telomere chromatid fusions increased consistently throughout the entire human life span. Our data, therefore, suggest that telomeric replication defects other than the end replication problem contribute to aging-associated telomere erosion in humans.
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Fernandes, Stina George, Rebecca Dsouza, Gouri Pandya, Anuradha Kirtonia, Vinay Tergaonkar, Sook Y. Lee, Manoj Garg i Ekta Khattar. "Role of Telomeres and Telomeric Proteins in Human Malignancies and Their Therapeutic Potential". Cancers 12, nr 7 (14.07.2020): 1901. http://dx.doi.org/10.3390/cancers12071901.
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Telomeres are the ends of linear chromosomes comprised of repetitive nucleotide sequences in humans. Telomeres preserve chromosomal stability and genomic integrity. Telomere length shortens with every cell division in somatic cells, eventually resulting in replicative senescence once telomere length becomes critically short. Telomere shortening can be overcome by telomerase enzyme activity that is undetectable in somatic cells, while being active in germline cells, stem cells, and immune cells. Telomeres are bound by a shelterin complex that regulates telomere lengthening as well as protects them from being identified as DNA damage sites. Telomeres are transcribed by RNA polymerase II, and generate a long noncoding RNA called telomeric repeat-containing RNA (TERRA), which plays a key role in regulating subtelomeric gene expression. Replicative immortality and genome instability are hallmarks of cancer and to attain them cancer cells exploit telomere maintenance and telomere protection mechanisms. Thus, understanding the role of telomeres and their associated proteins in cancer initiation, progression and treatment is very important. The present review highlights the critical role of various telomeric components with recently established functions in cancer. Further, current strategies to target various telomeric components including human telomerase reverse transcriptase (hTERT) as a therapeutic approach in human malignancies are discussed.
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Calado, Rodrigo T., Solomon A. Graf i Neal S. Young. "Telomeric Recombination in Lymphocytes Implicates ALT, an Alternative Mechanism for Telomere Length Maintenance, in Normal Human Hematopoietic Cells." Blood 110, nr 11 (16.11.2007): 1332. http://dx.doi.org/10.1182/blood.v110.11.1332.1332.
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Abstract Telomeres are the very ends of chromosomes and protect the genome from recombination, end-to-end-fusion, and recognition as damaged DNA. Telomeres are eroded with each cell division, eventually reaching such critically short length as to cause cell cycle arrest, apoptosis, or genomic instability. In most highly proliferative cells, including hematopoietic stem cells and T lymphocytes, telomere attrition is countered by telomere extension by telomerase reverse transcriptase complex. The majority of cancer cells also express telomerase, which maintains telomere length and allows indefinite cell proliferation. However, about 10% of tumors maintain telomere length in the absence of telomerase by mechanisms collectively termed alternative lengthening of telomeres (ALT). ALT mainly acts through asymmetrical exchange of telomeric material between chromosomes or sister chromatids, producing one daughter-cell with short telomeres and a limited life-span and its sister with long telomeres and higher proliferative capacity. To date, ALT has only been reported in cancer cells or through genetic engineering of mammalian cells. Here we investigated whether ALT mechanisms were active in hematopoietic cells using chromosome orientation fluorescent in situ hybridization (CO-FISH). In standard FISH, a telomeric probe produces fours signals per chromosome, one at each end of the two chromatids. Using CO-FISH, the newly synthesized DNA strand is fragmented by BrdU incorporation and UV light exposure and then digested by exonucleases. In CO-FISH, a telomeric probe produces two signals only, one at each end of the chromosome; in the presence of telomeric recombination, the telomeric signal is split, generating more than two signals per chromosome. Peripheral blood lymphocytes from three healthy volunteers, normal human fibroblasts, K562 cells, telomerase-positive HeLa cells (known to be negative for ALT),and telomerase-negative VA13 cells (known to be positive for ALT) were investigated for telomeric sister chromatid exchange (t-SCE); at least 20 metaphases per cell type were examined. Cultured peripheral blood lymphocytes and VA13 cells both showed increased levels of telomeric sister chromatid exchange in comparison to the other cells (P=0.0001): telomeric probe generated 2.62±0.11 telomeric signals/chromosome in lymphocytes; 2.23±0.04 in VA13 cells; 2.09±0.01 in HeLa cells; 2.02±0.01 in K562 cells; and 2.02±0.01 in human skin fibroblasts. Staining incorporated-BrdU over 24 hours and evaluation of “harlequin” chromosomes point to a similar rate of genomic sister chromatid exchange in lymphocytes, VA13 cells, and HeLa cells, suggesting that high chromatid exchange is confined to the telomeric region. A physical association between promyelocytic leukemia protein (PML) and telomeres is characteristic of some ALT-positive cells, but confocal microscopy failed to co-localize the telomeric probe and anti-PML monoclonal antibody in peripheral blood lymphocytes, suggesting that t-SCE in lymphocytes is not mediated by PML. This is the first demonstration of ALT activation in normal mammalian cells. ALT may be activated in peripheral blood lymphocytes as a complementary mechanism to maintain telomere length, and may explain the differences in age-related telomere shortening observed between lymphocytes and granulocytes.
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Amato, Roberta, Martina Valenzuela, Francesco Berardinelli, Erica Salvati, Carmen Maresca, Stefano Leone, Antonio Antoccia i Antonella Sgura. "G-quadruplex Stabilization Fuels the ALT Pathway in ALT-positive Osteosarcoma Cells". Genes 11, nr 3 (13.03.2020): 304. http://dx.doi.org/10.3390/genes11030304.
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Most human tumors maintain telomere lengths by telomerase, whereas a portion of them (10–15%) uses a mechanism named alternative lengthening of telomeres (ALT). The telomeric G-quadruplex (G4) ligand RHPS4 is known for its potent antiproliferative effect, as shown in telomerase-positive cancer models. Moreover, RHPS4 is also able to reduce cell proliferation in ALT cells, although the influence of G4 stabilization on the ALT mechanism has so far been poorly investigated. Here we show that sensitivity to RHPS4 is comparable in ALT-positive (U2OS; SAOS-2) and telomerase-positive (HOS) osteosarcoma cell lines, unlinking the telomere maintenance mechanism and RHPS4 responsiveness. To investigate the impact of G4 stabilization on ALT, the cardinal ALT hallmarks were analyzed. A significant induction of telomeric doublets, telomeric clusterized DNA damage, ALT-associated Promyelocytic Leukaemia-bodies (APBs), telomere sister chromatid exchanges (T-SCE) and c-circles was found exclusively in RHPS4-treated ALT cells. We surmise that RHPS4 affects ALT mechanisms through the induction of replicative stress that in turn is converted in DNA damage at telomeres, fueling recombination. In conclusion, our work indicates that RHPS4-induced telomeric DNA damage promotes overactivation of telomeric recombination in ALT cells, opening new questions on the therapeutic employment of G4 ligands in the treatment of ALT positive tumors.
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Gupta, Aditi, Bor-Jang Hwang, Daniel Benyamien-Roufaeil, Sara Jain, Sophie Liu, Rex Gonzales, Robert A. Brown, Michal Zalzman i A.-Lien Lu. "Mammalian MutY Homolog (MYH or MUTYH) is Critical for Telomere Integrity under Oxidative Stress". OBM Geriatrics 6, nr 2 (22.07.2021): 1. http://dx.doi.org/10.21926/obm.geriatr.2202196.
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Telomeres consist of special features and proteins to protect the ends of each chromosome from deterioration and fusion. The telomeric DNA repeats are highly susceptible to oxidative damage that can accelerate telomere shortening and affect telomere integrity. Several DNA repair factors including MYH/MUTYH DNA glycosylase, its interacting partners Rad9/Rad1/Hus1 checkpoint clamp, and SIRT6 aging regulator, are associated with the telomeres. MYH prevents C:G to A:T mutation by removing adenine mispaired with a frequent oxidative DNA lesion, 8-oxoguanine. Here, we show that hMYH knockout (KO) human HEK-293T cells are more sensitive to H2O2 treatment, have higher levels of DNA strand breaks and shorter telomeres than the control hMYH+/+ cells. SIRT6 foci increase at both the global genome and at telomeric regions in H2O2-treated hMYH+/+ cells. However, in untreated hMYH KO HEK-293T cells, SIRT6 foci only increase at the global genome, but not at the telomeric regions. In addition, the hMYH KO HEK-293T cells have increased extra-chromosomal and intra-chromosomal telomeres compared to the control cells, even in the absence of H2O2 treatment. After H2O2 treatment, the frequency of extra-chromosomal telomeres increased in control HEK-293T cells. Remarkably, in H2O2-treated hMYH KO cells, the frequencies of extra-chromosomal telomeres, intra-chromosomal telomeres, and telomere fusions are further increased. We further found that the sensitivity to H2O2 and shortened telomeres of hMYH KO cells, are restored by expressing wild-type hMYH, and partially rescued by expressing hMYHQ324H mutant (defective in Hus1 interaction only), but not by expressing hMYHV315A mutant (defective in both SIRT6 and Hus1 interactions). Thus, MYH interactions with SIRT6 and Hus1 are critical for maintaining cell viability and telomeric stability. Therefore, the failure to coordinate 8-oxoG repair is detrimental to telomere integrity.
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Gong, Yi, i Yie Liu. "R-Loops at Chromosome Ends: From Formation, Regulation, and Cellular Consequence". Cancers 15, nr 7 (6.04.2023): 2178. http://dx.doi.org/10.3390/cancers15072178.
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Telomeric repeat containing RNA (TERRA) is transcribed from subtelomeric regions to telomeres. TERRA RNA can invade telomeric dsDNA and form telomeric R-loop structures. A growing body of evidence suggests that TERRA-mediated R-loops are critical players in telomere length homeostasis. Here, we will review current knowledge on the regulation of R-loop levels at telomeres. In particular, we will discuss how the central player TERRA and its binding proteins modulate R-loop levels through various mechanisms. We will further provide an overview of the consequences of TERRA-mediated persistent or unscheduled R-loops at telomeres in human ALT cancers and other organisms, with a focus on telomere length regulation after replication interference-induced damage and DNA homologous recombination-mediated repair.
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Izumi, Hiroto, i Keiko Funa. "Telomere Function and the G-Quadruplex Formation are Regulated by hnRNP U". Cells 8, nr 5 (28.04.2019): 390. http://dx.doi.org/10.3390/cells8050390.
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We examine the role of the heterogenous ribonucleoprotein U (hnRNP U) as a G-quadruplex binding protein in human cell lines. Hypothesizing that hnRNP U is associated with telomeres, we investigate what other telomere-related functions it may have. Telomeric G-quadruplexes have been fully characterized in vitro, but until now no clear evidence of their function or in vivo interactions with proteins has been revealed in mammalian cells. Techniques used were immunoprecipitation, DNA pull-down, binding assay, and Western blots. We identified hnRNP U as a G-quadruplex binding protein. Immunoprecipitations disclosed that endogenous hnRNP U associates with telomeres, and DNA pull-downs showed that the hnRNP U C-terminus specifically binds telomeric G-quadruplexes. We have compared the effect of telomere repeat containing RNA (TERRA) on binding between hnRNP U and telomeric (Tel) or single- stranded Tel (ssTel) oligonucleotides and found that ssTel binds stronger to TERRA than to Tel. We also show that hnRNP U prevents replication protein A (RPA) accumulation at telomeres, and the recognition of telomeric ends by hnRNP suggests that a G-quadruplex promoting protein regulates its accessibility. Thus, hnRNP U-mediated formation has important functions for telomere biology.
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Soman, Aghil, Chong Wai Liew, Hsiang Ling Teo, Nikolay V. Berezhnoy, Vincent Olieric, Nikolay Korolev, Daniela Rhodes i Lars Nordenskiöld. "The human telomeric nucleosome displays distinct structural and dynamic properties". Nucleic Acids Research 48, nr 10 (6.05.2020): 5383–96. http://dx.doi.org/10.1093/nar/gkaa289.
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Abstract Telomeres protect the ends of our chromosomes and are key to maintaining genomic integrity during cell division and differentiation. However, our knowledge of telomeric chromatin and nucleosome structure at the molecular level is limited. Here, we aimed to define the structure, dynamics as well as properties in solution of the human telomeric nucleosome. We first determined the 2.2 Å crystal structure of a human telomeric nucleosome core particle (NCP) containing 145 bp DNA, which revealed the same helical path for the DNA as well as symmetric stretching in both halves of the NCP as that of the 145 bp ‘601’ NCP. In solution, the telomeric nucleosome exhibited a less stable and a markedly more dynamic structure compared to NCPs containing DNA positioning sequences. These observations provide molecular insights into how telomeric DNA forms nucleosomes and chromatin and advance our understanding of the unique biological role of telomeres.
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Yang, B. C., G. S. Im, Y. H. Kim, J. W. Choi, Y. S. Park, H. W. Hwang, S. C. Joo i in. "79 THE AMOUNT OF TELOMERIC DNA IN CLONED CATTLE AND THEIR CALVES IS LESS THAN THAT OF AGE MATCHED CATTLE". Reproduction, Fertility and Development 18, nr 2 (2006): 148. http://dx.doi.org/10.1071/rdv18n2ab79.
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A telomere is a structure consisting of tandem repeats sequences of (TTAGGG)n at the end of the eukaryotic chromosome. Telomere lengths in animals vary by species, age, and tissues, as well as environment. This experiment concentrated on the amount of telomeric DNA in cloned cattle, their calves, and age-matched normal cattle. Using somatic cell nuclear transfer (SCNT), we had obtained 16 cloned Korean Native cows derived from ear skin fibroblasts and two cloned bulls from fetal fibroblasts. In addition, four female calves were produced from each cloned cow by artificial insemination. Control cattle selected to have matched age and the same raising place served as counter-parts of cloned the cattle in this study. The lymphocytes of all cloned cattle, their calves, and the age-matched controls were examined for telomere quantity. The amount of telomeric DNA was analyzed by quantitative fluorescence after in situ hybridization (Q-FISH) with a human telomeric DNA repeat probe. A minimum of 100 interphase nuclei from each set of harvests was studied to determine the mean and medium percentages of telomeric DNA using the MetaMorph Imaging System (Universal Imaging Co., West Chester, PA, USA). The amount of telomeric DNA obtained was found to decrease in cloned and control animals during growth. The amounts of telomeric DNA in cloned cattle from both ear skin fibroblasts (n = 16) and fetal fibroblasts (n = 2) was less than that of age-matched controls (P < 0.01). Surprisingly, the amount of telomeric DNA of calves from cloned cattle was also lower than that of age matched controls (n = 4, P < 0.01). The results showed a remarkable difference in the amount of telomeric DNA between SCNT cloned cattle and normal cattle. In conclusion, the telomeres of cloned animal and their calves are significantly shorter than those of normal cattle. Moreover, the short telomeres in calves could be inherited from their cloned mothers.
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Wu, Guanhui, Luying Chen, Wenting Liu i Danzhou Yang. "Molecular Recognition of the Hybrid-Type G-Quadruplexes in Human Telomeres". Molecules 24, nr 8 (22.04.2019): 1578. http://dx.doi.org/10.3390/molecules24081578.
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G-quadruplex (G4) DNA secondary structures formed in human telomeres have been shown to inhibit cancer-specific telomerase and alternative lengthening of telomere (ALT) pathways. Thus, human telomeric G-quadruplexes are considered attractive targets for anticancer drugs. Human telomeric G-quadruplexes are structurally polymorphic and predominantly form two hybrid-type G-quadruplexes, namely hybrid-1 and hybrid-2, under physiologically relevant solution conditions. To date, only a handful solution structures are available for drug complexes of human telomeric G-quadruplexes. In this review, we will describe two recent solution structural studies from our labs. We use NMR spectroscopy to elucidate the solution structure of a 1:1 complex between a small molecule epiberberine and the hybrid-2 telomeric G-quadruplex, and the structures of 1:1 and 4:2 complexes between a small molecule Pt-tripod and the hybrid-1 telomeric G-quadruplex. Structural information of small molecule complexes can provide important information for understanding small molecule recognition of human telomeric G-quadruplexes and for structure-based rational drug design targeting human telomeric G-quadruplexes.
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Xu, Lifeng, i Elizabeth H. Blackburn. "Human Rif1 protein binds aberrant telomeres and aligns along anaphase midzone microtubules". Journal of Cell Biology 167, nr 5 (6.12.2004): 819–30. http://dx.doi.org/10.1083/jcb.200408181.
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We identified and characterized a human orthologue of Rif1 protein, which in budding yeast interacts in vivo with the major duplex telomeric DNA binding protein Rap1p and negatively regulates telomere length. Depletion of hRif1 by RNA interference in human cancer cells impaired cell growth but had no detectable effect on telomere length, although hRif1 overexpression in S. cerevisiae interfered with telomere length control, in a manner specifically dependent on the presence of yeast Rif1p. No localization of hRif1 on normal human telomeres, or interaction with the human telomeric proteins TRF1, TRF2, or hRap1, was detectable. However, hRif1 efficiently translocated to telomerically located DNA damage foci in response to the synthesis of aberrant telomeres directed by mutant-template telomerase RNA. The hRif1 level rose during late S/G2 but hRif1 was not visible on chromosomes in metaphase and anaphase; however, notably, specifically during early anaphase, hRif1 aligned along a subset of the midzone microtubules between the separating chromosomes. In telophase, hRif1 localized to chromosomes, and in interphase, it was intranuclear. These results define a novel subcellular localization behavior for hRif1 during the cell cycle.
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Bassham, Susan, Aaron Beam i Janis Shampay. "Telomere Variation in Xenopus laevis". Molecular and Cellular Biology 18, nr 1 (1.01.1998): 269–75. http://dx.doi.org/10.1128/mcb.18.1.269.
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ABSTRACT Eukaryotic telomeres are variable at several levels, from the length of the simple sequence telomeric repeat tract in different cell types to the presence or number of telomere-adjacent DNA sequence elements in different strains or individuals. We have investigated the sequence organization of Xenopus laevis telomeres by use of the vertebrate telomeric repeat (TTAGGG) n and blot hybridization analysis. The (TTAGGG) n -hybridizing fragments, which ranged from less than 10 to over 50 kb with frequently cutting enzymes, defined a pattern that was polymorphic between individuals. BAL 31 exonuclease treatment confirmed that these fragments were telomeric. The polymorphic fragments analyzed did not hybridize to 5S RNA sequences, which are telomeric according to in situ hybridization. When telomeric fragments from offspring (whole embryos) were compared to those from the spleens of the parents, the inheritance pattern of some bands was found to be unusual. Furthermore, in one cross, the telomeres of the embryo were shorter than the telomeres of the parents’ spleen, and in another, the male’s testis telomeres were shorter than those of the male’s spleen. Our data are consistent with a model for chromosome behavior that involves a significant amount of DNA rearrangement at telomeres and suggest that length regulation ofXenopus telomeres is different from that observed forMus spretus and human telomeres.
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Bryan, Tracy M. "G-Quadruplexes at Telomeres: Friend or Foe?" Molecules 25, nr 16 (13.08.2020): 3686. http://dx.doi.org/10.3390/molecules25163686.
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Telomeres are DNA-protein complexes that cap and protect the ends of linear chromosomes. In almost all species, telomeric DNA has a G/C strand bias, and the short tandem repeats of the G-rich strand have the capacity to form into secondary structures in vitro, such as four-stranded G-quadruplexes. This has long prompted speculation that G-quadruplexes play a positive role in telomere biology, resulting in selection for G-rich tandem telomere repeats during evolution. There is some evidence that G-quadruplexes at telomeres may play a protective capping role, at least in yeast, and that they may positively affect telomere maintenance by either the enzyme telomerase or by recombination-based mechanisms. On the other hand, G-quadruplex formation in telomeric DNA, as elsewhere in the genome, can form an impediment to DNA replication and a source of genome instability. This review summarizes recent evidence for the in vivo existence of G-quadruplexes at telomeres, with a focus on human telomeres, and highlights some of the many unanswered questions regarding the location, form, and functions of these structures.
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Gu, Wei, Zihan Lin, Shengchao Zhao, Guanzhen Wang, Ziyi Shen, Wei Liu, Yi Cai, Kaibo Wang, Chunpeng Craig Wan i Tingdong Yan. "Research Progress on G-Quadruplexes in Human Telomeres and Human Telomerase Reverse Transcriptase (hTERT) Promoter". Oxidative Medicine and Cellular Longevity 2022 (6.06.2022): 1–11. http://dx.doi.org/10.1155/2022/2905663.
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The upregulation telomerase activity is observed in over 85-90% of human cancers and provides an attractive target for cancer therapies. The high guanine content in the telomere DNA sequences and the hTERT promoter can form G-quadruplexes (G4s). Small molecules targeting G4s in telomeres and hTERT promoter could stabilize the G4s and inhibit hTERT expression and telomere extension. Several G4 ligands have shown inhibitory effects in cancer cells and xenograft mouse models, indicating these ligands have a potential for cancer therapies. The current review article describes the concept of the telomere, telomerase, and G4s. Moreover, the regulation of telomerase and G4s in telomeres and hTERT promoter is discussed as well. The summary of the small molecules targeting G4s in telomeric DNA sequences and the hTERT promoter will also be shown.
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Vinayagamurthy, Soujanya, Akansha Ganguly i Shantanu Chowdhury. "Extra-telomeric impact of telomeres: Emerging molecular connections in pluripotency or stemness". Journal of Biological Chemistry 295, nr 30 (22.05.2020): 10245–54. http://dx.doi.org/10.1074/jbc.rev119.009710.
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Telomeres comprise specialized nucleic acid–protein complexes that help protect chromosome ends from DNA damage. Moreover, telomeres associate with subtelomeric regions through looping. This results in altered expression of subtelomeric genes. Recent observations further reveal telomere length–dependent gene regulation and epigenetic modifications at sites spread across the genome and distant from telomeres. This regulation is mediated through the telomere-binding protein telomeric repeat–binding factor 2 (TRF2). These observations suggest a role of telomeres in extra-telomeric functions. Most notably, telomeres have a broad impact on pluripotency and differentiation. For example, cardiomyocytes differentiate with higher efficacy from induced pluripotent stem cells having long telomeres, and differentiated cells obtained from human embryonic stem cells with relatively long telomeres have a longer lifespan. Here, we first highlight reports on these two seemingly distinct research areas: the extra-telomeric role of telomere-binding factors and the role of telomeres in pluripotency/stemness. On the basis of the observations reported in these studies, we draw attention to potential molecular connections between extra-telomeric biology and pluripotency. Finally, in the context of the nonlocal influence of telomeres on pluripotency and stemness, we discuss major opportunities for progress in molecular understanding of aging-related disorders and neurodegenerative diseases.
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Cong, Yu-Sheng, Woodring E. Wright i Jerry W. Shay. "Human Telomerase and Its Regulation". Microbiology and Molecular Biology Reviews 66, nr 3 (wrzesień 2002): 407–25. http://dx.doi.org/10.1128/mmbr.66.3.407-425.2002.
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SUMMARY The telomere is a special functional complex at the end of linear eukaryotic chromosomes, consisting of tandem repeat DNA sequences and associated proteins. It is essential for maintaining the integrity and stability of linear eukaryotic genomes. Telomere length regulation and maintenance contribute to normal human cellular aging and human diseases. The synthesis of telomeres is mainly achieved by the cellular reverse transcriptase telomerase, an RNA-dependent DNA polymerase that adds telomeric DNA to telomeres. Expression of telomerase is usually required for cell immortalization and long-term tumor growth. In humans, telomerase activity is tightly regulated during development and oncogenesis. The modulation of telomerase activity may therefore have important implications in antiaging and anticancer therapy. This review describes the currently known components of the telomerase complex and attempts to provide an update on the molecular mechanisms of human telomerase regulation.
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Mentegari, Elisa, Federica Bertoletti, Miroslava Kissova, Elisa Zucca, Silvia Galli, Giulia Tagliavini, Anna Garbelli i in. "A Role for Human DNA Polymerase λ in Alternative Lengthening of Telomeres". International Journal of Molecular Sciences 22, nr 5 (27.02.2021): 2365. http://dx.doi.org/10.3390/ijms22052365.
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Telomerase negative cancer cell types use the Alternative Lengthening of Telomeres (ALT) pathway to elongate telomeres ends. Here, we show that silencing human DNA polymerase (Pol λ) in ALT cells represses ALT activity and induces telomeric stress. In addition, replication stress in the absence of Pol λ, strongly affects the survival of ALT cells. In vitro, Pol λ can promote annealing of even a single G-rich telomeric repeat to its complementary strand and use it to prime DNA synthesis. The noncoding telomeric repeat containing RNA TERRA and replication protein A negatively regulate this activity, while the Protection of Telomeres protein 1 (POT1)/TPP1 heterodimer stimulates Pol λ. Pol λ associates with telomeres and colocalizes with TPP1 in cells. In summary, our data suggest a role of Pol λ in the maintenance of telomeres by the ALT mechanism.
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Cesare, Anthony J., i Jack D. Griffith. "Telomeric DNA in ALT Cells Is Characterized by Free Telomeric Circles and Heterogeneous t-Loops". Molecular and Cellular Biology 24, nr 22 (15.11.2004): 9948–57. http://dx.doi.org/10.1128/mcb.24.22.9948-9957.2004.
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ABSTRACT A prerequisite for cellular immortalization in human cells is the elongation of telomeres through the upregulation of telomerase or by the alternative lengthening of telomeres (ALT) pathway. In this study, telomere structure in multiple ALT cell lines was examined by electron microscopy. Nuclei were isolated from GM847, GM847-Tert, and WI-38 VA13 ALT cells, psoralen photo-cross-linked in situ, and the telomere restriction fragments were purified by gel filtration chromatography. Examination of telomere-enriched fractions revealed frequent extrachromosomal circles, ranging from 0.7 to 56.8 kb. t-loops were also observed, with the loop portion ranging from 0.5 to 70.2 kb. The total length of the loop plus tail of the t-loops corresponded to the telomere restriction fragment length from the ALT cell lines as determined by pulsed-field gel electrophoresis. The presence of extrachromosomal circles containing telomeric DNA was confirmed by two-dimensional pulsed-field gel electrophoresis. These results show that extrachromosomal telomeric DNA circles are present in ALT nuclei and suggest a roll-and-spread mechanism of telomere elongation similar to that seen in previous observations of multiple yeast species. Results presented here also indicate that expression of telomerase in GM847 cells does not affect t-loop or extrachromosomal circle formation.
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Smogorzewska, Agata, Bas van Steensel, Alessandro Bianchi, Stefan Oelmann, Matthias R. Schaefer, Gisela Schnapp i Titia de Lange. "Control of Human Telomere Length by TRF1 and TRF2". Molecular and Cellular Biology 20, nr 5 (1.03.2000): 1659–68. http://dx.doi.org/10.1128/mcb.20.5.1659-1668.2000.
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ABSTRACT Telomere length in human cells is controlled by a homeostasis mechanism that involves telomerase and the negative regulator of telomere length, TRF1 (TTAGGG repeat binding factor 1). Here we report that TRF2, a TRF1-related protein previously implicated in protection of chromosome ends, is a second negative regulator of telomere length. Overexpression of TRF2 results in the progressive shortening of telomere length, similar to the phenotype observed with TRF1. However, while induction of TRF1 could be maintained over more than 300 population doublings and resulted in stable, short telomeres, the expression of exogenous TRF2 was extinguished and the telomeres eventually regained their original length. Consistent with their role in measuring telomere length, indirect immunofluorescence indicated that both TRF1 and TRF2 bind to duplex telomeric DNA in vivo and are more abundant on telomeres with long TTAGGG repeat tracts. Neither TRF1 nor TRF2 affected the expression level of telomerase. Furthermore, the presence of TRF1 or TRF2 on a short linear telomerase substrate did not inhibit the enzymatic activity of telomerase in vitro. These findings are consistent with the recently proposed t loop model of telomere length homeostasis in which telomerase-dependent telomere elongation is blocked by sequestration of the 3′ telomere terminus in TRF1- and TRF2-induced telomeric loops.
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Bettin, Nicole, Claudio Oss Pegorar i Emilio Cusanelli. "The Emerging Roles of TERRA in Telomere Maintenance and Genome Stability". Cells 8, nr 3 (15.03.2019): 246. http://dx.doi.org/10.3390/cells8030246.
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The finding that transcription occurs at chromosome ends has opened new fields of study on the roles of telomeric transcripts in chromosome end maintenance and genome stability. Indeed, the ends of chromosomes are required to be protected from activation of DNA damage response and DNA repair pathways. Chromosome end protection is achieved by the activity of specific proteins that associate with chromosome ends, forming telomeres. Telomeres need to be constantly maintained as they are in a heterochromatic state and fold into specific structures (T-loops), which may hamper DNA replication. In addition, in the absence of maintenance mechanisms, chromosome ends shorten at every cell division due to limitations in the DNA replication machinery, which is unable to fully replicate the extremities of chromosomes. Altered telomere structure or critically short chromosome ends generate dysfunctional telomeres, ultimately leading to replicative senescence or chromosome instability. Telomere biology is thus implicated in multiple human diseases, including cancer. Emerging evidence indicates that a class of long noncoding RNAs transcribed at telomeres, known as TERRA for “TElomeric Repeat-containing RNA,” actively participates in the mechanisms regulating telomere maintenance and chromosome end protection. However, the molecular details of TERRA activities remain to be elucidated. In this review, we discuss recent findings on the emerging roles of TERRA in telomere maintenance and genome stability and their implications in human diseases.
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Mustafa, Golam, Sajad Shiekh, Keshav GC, Sanjaya Abeysirigunawardena i Hamza Balci. "Interrogating accessibility of telomeric sequences with FRET-PAINT: evidence for length-dependent telomere compaction". Nucleic Acids Research 49, nr 6 (10.03.2021): 3371–80. http://dx.doi.org/10.1093/nar/gkab067.
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Abstract Single-stranded telomeric overhangs are ∼200 nucleotides long and can form tandem G-quadruplex (GQ) structures, which reduce their accessibility to nucleases and proteins that activate DNA damage response. Whether these tandem GQs further stack to form compact superstructures, which may provide better protection for longer telomeres, is not known. We report single-molecule measurements where the accessibility of 24–144 nucleotide long human telomeric DNA molecules is interrogated by a short PNA molecule that is complementary to a single GGGTTA repeat, as implemented in the FRET-PAINT method. Binding of the PNA strand to available GGGTTA sequences results in discrete FRET bursts which were analyzed in terms of their dwell times, binding frequencies, and topographic distributions. The binding frequencies were greater for binding to intermediate regions of telomeric DNA compared to 3′- or 5′-ends, suggesting these regions are more accessible. Significantly, the binding frequency per telomeric repeat monotonically decreased with increasing telomere length. These results are consistent with telomeres forming more compact structures at longer lengths, reducing accessibility of these critical genomic sites.
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Baumann, Peter, Elaine Podell i Thomas R. Cech. "Human Pot1 (Protection of Telomeres) Protein: Cytolocalization, Gene Structure, and Alternative Splicing". Molecular and Cellular Biology 22, nr 22 (15.11.2002): 8079–87. http://dx.doi.org/10.1128/mcb.22.22.8079-8087.2002.
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ABSTRACT Fission yeast Pot1 (protection of telomeres) is a single-stranded telomeric DNA binding protein with a critical role in ensuring chromosome stability. A putative human homolog (hPot1) was previously identified, based on moderate sequence similarity with fission yeast Pot1 and telomere end-binding proteins from ciliated protozoa. Using indirect immunofluorescence, we show here that epitope-tagged hPot1 localizes to telomeres in interphase nuclei of human cells, consistent with a direct role in telomere end protection. The hPOT1 gene contains 22 exons, most of which are present in all cDNAs examined. However, four exons are subject to exon skipping in some transcripts, giving rise to five splice variants. Four of these are ubiquitously expressed, whereas the fifth appears to be specific to leukocytes. The resultant proteins vary significantly in their ability to form complexes with single-stranded telomeric DNA as judged by electrophoretic mobility shift assays. In addition to these splice variants, the Pot1 family is expanded by the identification of six more genes from diverse species. Pot1-like proteins have now been found in plants, animals, yeasts, and microsporidia.
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Pedram, Mehrdad, Carl N. Sprung, Qing Gao, Anthony W. I. Lo, Gloria E. Reynolds i John P. Murnane. "Telomere Position Effect and Silencing of Transgenes near Telomeres in the Mouse". Molecular and Cellular Biology 26, nr 5 (1.03.2006): 1865–78. http://dx.doi.org/10.1128/mcb.26.5.1865-1878.2006.
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ABSTRACT Reversible transcriptional silencing of genes located near telomeres, termed the telomere position effect (TPE), is well characterized in Saccharomyces cerevisiae. TPE has also been observed in human tumor cell lines, but its function remains unknown. To investigate TPE in normal mammalian cells, we developed clones of mouse embryonic stem (ES) cells that contain single-copy marker genes integrated adjacent to different telomeres. Analysis of these telomeric transgenes demonstrated that they were expressed at very low levels compared to the same transgenes integrated at interstitial sites. Similar to the situation in yeast, but in contrast to studies with human tumor cell lines, TPE in mouse ES cells was not reversed with trichostatin A. Prolonged culturing without selection resulted in extensive DNA methylation and complete silencing of telomeric transgenes, which could be reversed by treatment with 5-azacytidine. Thus, complete silencing of the telomeric transgenes appears to involve a two-step process in which the initial repression is reinforced by DNA methylation. Extensive methylation of the telomeric transgenes was also observed in various tissues and embryonic fibroblasts isolated from transgenic mice. In contrast, telomeric transgenes were not silenced in ES cell lines isolated from 3-day-old preimplantation embryos, consistent with the hypothesis that TPE plays a role in the development of the embryo.
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D'Souza, Yasmin, Tsz Wai Chu i Chantal Autexier. "A translocation-defective telomerase with low levels of activity and processivity stabilizes short telomeres and confers immortalization". Molecular Biology of the Cell 24, nr 9 (maj 2013): 1469–79. http://dx.doi.org/10.1091/mbc.e12-12-0889.
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Short, repetitive, G-rich telomeric sequences are synthesized by telomerase, a ribonucleoprotein consisting of telomerase reverse transcriptase (TERT) and an integrally associated RNA. Human TERT (hTERT) can repetitively reverse transcribe its RNA template, acting processively to add multiple telomeric repeats onto the same substrate. We investigated whether certain threshold levels of telomerase activity and processivity are required to maintain telomere function and immortalize human cells with limited lifespan. We assessed hTERT variants with mutations in motifs implicated in processivity and interaction with DNA, namely the insertion in fingers domain (V791Y), and the E primer grip motif (W930F). hTERT-W930F and hTERT-V791Y reconstitute reduced levels of DNA synthesis and processivity compared with wild-type telomerase. Of interest, hTERT-W930F is more defective in translocation than hTERT-V791Y. Nonetheless, hTERT-W930F, but not hTERT-V791Y, immortalizes limited-lifespan human cells. Both hTERT-W930F– and hTERT-V791Y–expressing cells harbor short telomeres, measured as signal free ends (SFEs), yet SFEs persist only in hTERT-V791Y cells, which undergo apoptosis, likely as a consequence of a defect in recruitment of hTERT-V791Y to telomeres. Our study is the first to demonstrate that low levels of DNA synthesis—on the order of 20% of wild-type telomerase levels—and extension of as few as three telomeric repeats are sufficient to maintain functional telomeres and immortalize limited-lifespan human cells.
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De Vitis, Marco, Francesco Berardinelli, Elisa Coluzzi, Jessica Marinaccio, Roderick J. O’Sullivan i Antonella Sgura. "X-rays Activate Telomeric Homologous Recombination Mediated Repair in Primary Cells". Cells 8, nr 7 (12.07.2019): 708. http://dx.doi.org/10.3390/cells8070708.
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Cancer cells need to acquire telomere maintenance mechanisms in order to counteract progressive telomere shortening due to multiple rounds of replication. Most human tumors maintain their telomeres expressing telomerase whereas the remaining 15%–20% utilize the alternative lengthening of telomeres (ALT) pathway. Previous studies have demonstrated that ionizing radiations (IR) are able to modulate telomere lengths and to transiently induce some of the ALT-pathway hallmarks in normal primary fibroblasts. In the present study, we investigated the telomere length modulation kinetics, telomeric DNA damage induction, and the principal hallmarks of ALT over a period of 13 days in X-ray-exposed primary cells. Our results show that X-ray-treated cells primarily display telomere shortening and telomeric damage caused by persistent IR-induced oxidative stress. After initial telomere erosion, we observed a telomere elongation that was associated to the transient activation of a homologous recombination (HR) based mechanism, sharing several features with the ALT pathway observed in cancer cells. Data indicate that telomeric damage activates telomeric HR-mediated repair in primary cells. The characterization of HR-mediated telomere repair in normal cells may contribute to the understanding of the ALT pathway and to the identification of novel strategies in the treatment of ALT-positive cancers.
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Stock, Amanda, Kun Wang, Chengyu Liu, Ross McDevitt, Chongkui Sun, Yi Gong i Yie Liu. "Age-Related Phenotypes Linked to Aberrant Expression and Localization of a Telomeric Protein". Innovation in Aging 5, Supplement_1 (1.12.2021): 661–62. http://dx.doi.org/10.1093/geroni/igab046.2498.
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Abstract Telomere attrition is associated with telomere biology disorders and age-related diseases. In telomere biology disorders, telomere uncapping induces a DNA damage response that evokes cell death or senescence. However, a causal mechanism for telomere attrition in age-related diseases remains elusive. Telomere capping and integrity are maintained by shelterin, a six-protein complex. Rap1 is the only shelterin member that is not required for telomere capping and is expressed at non-telomeric genomic and cytosolic regions. The objective of this study was to determine aberrant phenotypes attributed to non-telomeric Rap1. To test this, we generated a Rap1 mutant knock-in (KI) mouse model using CRISPR/Cas9 editing, in which Rap1 at telomeres is prevented, leaving only non-telomeric Rap1. Cell fractionation/western blotting of primary fibroblasts from Rap1 KI mice demonstrated decreased Rap1 expression and Rap1 re-localization off telomeres, with an altered cellular distribution. This same difference in Rap1 is also observed in human cells with telomere erosion, indicating that aberrant Rap1 in our model may recapitulate Rap1 in aging and human telomere biology disorders. Compared to wild-type control mice, Rap1 KI mice exhibited increased body weight, altered cytokine levels, behavioral deficits, and decreased lifespan. In conclusion, our results reveal a novel mechanism by which telomere shortening may contribute to age-related pathologies by disrupting Rap1 expression and cell localization.
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Schmidt, Jens C., Arthur J. Zaug, Regina Kufer i Thomas R. Cech. "Dynamics of human telomerase recruitment depend on template-telomere base pairing". Molecular Biology of the Cell 29, nr 7 (kwiecień 2018): 869–80. http://dx.doi.org/10.1091/mbc.e17-11-0637.
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The reverse transcriptase telomerase adds telomeric repeats to chromosome ends to counteract telomere shortening and thereby assures genomic stability in dividing human cells. Key parameters in telomere homeostasis are the frequency with which telomerase engages the chromosome end and the number of telomeric repeats it adds during each association event. To study telomere elongation in vivo, we have established a live-cell imaging assay to track individual telomerase ribonucleoproteins in CRISPR-edited HeLa cells. Using this assay and the drug imetelstat, which is a competitive inhibitor of telomeric DNA binding, we demonstrate that stable association of telomerase with the single-stranded overhang of the chromosome end requires telomerase-DNA base pairing. Furthermore, we show that telomerase processivity contributes to telomere elongation in vivo. Together, these findings provide new insight into the dynamics of telomerase recruitment and the importance of processivity in maintaining telomere length in human cancer cells.
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Yang, B. C., G. S. Im, Y. H. Kim, D. H. Kim, S. H. Bae, Y. G. Ko, H. H. Seong, S. H. Shon i B. S. Yang. "99 AMOUNT OF TELOMERIC DNA IN GROWING CLONED CATTLE, THEIR PROGENY, AND THEIR ORGANS". Reproduction, Fertility and Development 19, nr 1 (2007): 167. http://dx.doi.org/10.1071/rdv19n1ab99.
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Telomeres are specialized nucleoprotein complexes at the termini of linear chromosomes that are composed of TTAGGG sequences in vertebrates. Telomere lengths in animals vary with species, age, tissue types, environment, and cloning. The experiment conducted emphasized the amount of telomeric DNA in the lymphocytes and organs of growing cloned cattle and their second and third generations. Using somatic cell nuclear transfer (SCNT), 16 cloned (Generation, clone G1) Korean Native cows were obtained from ear skin fibroblasts and 2 cloned bulls from fetal fibroblasts. In addition, 3 females and 2 males (clone G2) were produced from each cloned cow by artificial insemination (AI). A third generation calf (clone G3) was derived from clone G2 by AI. The lymphocytes of all cloned cattle (G1), their offspring (G2), and age-matched controls were examined 3 times at 6-month intervals whereas G3 was examined only once. The amount of telomeric DNA was analyzed by quantitative fluorescence in situ hybridization (Q-FISH) with a human telomeric DNA repeat probe. A minimum of 100 interphase nuclei from each set of harvests was studied to determine the mean and medium percentages of telomeric DNA using MetaMorph Imaging System (Universal Imaging Co, West Chester, PA, USA). The amounts of telomeric DNA in cloned cattle from both ear skin fibroblasts (female, n = 16) and fetal fibroblasts (male, n = 2) were less than those of age-matched controls (P < 0.01). Additionally, irrespective of gender, the telomeres in the clone G2 and G3 calves were lower than in controls (n = 6; P < 0.05). Furthermore, in the cloned cattle, the amount of telomeric DNA was drastically less than that of control animals during growth. Moreover, we examined the internal organs and tissues of a cloned cow at 30 months. The telomeres of leukocytes, cerebrum, spleen, cerebellum, hindbrain, and lung were a little smaller, whereas those of the liver, pituitary, kidney, and heart were slightly larger, than those of an age-matched cow. The results showed a remarkable difference in the amount of telomeric DNA between SCNT cloned cattle and normal cattle. Although the organs and tissues were not correlated, the amount of telomeres rapidly decreased with growth in cloned cattle. Conclusively, the telomeres of a cloned animal and its calves were significantly shorter than those of control cattle, and the short telomeres in calves could be inherited by progeny from their cloned mother.
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Wu, Yangxiu, Rebecca C. Poulos i Roger R. Reddel. "Role of POT1 in Human Cancer". Cancers 12, nr 10 (24.09.2020): 2739. http://dx.doi.org/10.3390/cancers12102739.
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Telomere abnormalities facilitate cancer development by contributing to genomic instability and cellular immortalization. The Protection of Telomeres 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex. It directly binds to single-stranded telomeric DNA, protecting chromosomal ends from an inappropriate DNA damage response, and plays a role in telomere length regulation. Alterations of POT1 have been detected in a range of cancers. Here, we review the biological functions of POT1, the prevalence of POT1 germline and somatic mutations across cancer predisposition syndromes and tumor types, and the dysregulation of POT1 expression in cancers. We propose a framework for understanding how POT1 abnormalities may contribute to oncogenesis in different cell types. Finally, we summarize the clinical implications of POT1 alterations in the germline and in cancer, and possible approaches for the development of targeted cancer therapies.
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Diman, Aurélie, Joanna Boros, Florian Poulain, Julie Rodriguez, Marin Purnelle, Harikleia Episkopou, Luc Bertrand, Marc Francaux, Louise Deldicque i Anabelle Decottignies. "Nuclear respiratory factor 1 and endurance exercise promote human telomere transcription". Science Advances 2, nr 7 (lipiec 2016): e1600031. http://dx.doi.org/10.1126/sciadv.1600031.
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DNA breaks activate the DNA damage response and, if left unrepaired, trigger cellular senescence. Telomeres are specialized nucleoprotein structures that protect chromosome ends from persistent DNA damage response activation. Whether protection can be enhanced to counteract the age-dependent decline in telomere integrity is a challenging question. Telomeric repeat–containing RNA (TERRA), which is transcribed from telomeres, emerged as important player in telomere integrity. However, how human telomere transcription is regulated is still largely unknown. We identify nuclear respiratory factor 1 and peroxisome proliferator–activated receptor γ coactivator 1α as regulators of human telomere transcription. In agreement with an upstream regulation of these factors by adenosine 5′-monophosphate (AMP)–activated protein kinase (AMPK), pharmacological activation of AMPK in cancer cell lines or in normal nonproliferating myotubes up-regulated TERRA, thereby linking metabolism to telomere fitness. Cycling endurance exercise, which is associated with AMPK activation, increased TERRA levels in skeletal muscle biopsies obtained from 10 healthy young volunteers. The data support the idea that exercise may protect against aging.
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Carrino, Simone, Christopher D. Hennecker, Ana C. Murrieta i Anthony Mittermaier. "Frustrated folding of guanine quadruplexes in telomeric DNA". Nucleic Acids Research 49, nr 6 (8.03.2021): 3063–76. http://dx.doi.org/10.1093/nar/gkab140.
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Abstract Human chromosomes terminate in long, single-stranded, DNA overhangs of the repetitive sequence (TTAGGG)n. Sets of four adjacent TTAGGG repeats can fold into guanine quadruplexes (GQ), four-stranded structures that are implicated in telomere maintenance and cell immortalization and are targets in cancer therapy. Isolated GQs have been studied in detail, however much less is known about folding in long repeat sequences. Such chains adopt an enormous number of configurations containing various arrangements of GQs and unfolded gaps, leading to a highly frustrated energy landscape. To better understand this phenomenon, we used mutagenesis, thermal melting, and global analysis to determine stability, kinetic, and cooperativity parameters for GQ folding within chains containing 8–12 TTAGGG repeats. We then used these parameters to simulate the folding of 32-repeat chains, more representative of intact telomeres. We found that a combination of folding frustration and negative cooperativity between adjacent GQs increases TTAGGG unfolding by up to 40-fold, providing an abundance of unfolded gaps that are potential binding sites for telomeric proteins. This effect was most pronounced at the chain termini, which could promote telomere extension by telomerase. We conclude that folding frustration is an important and largely overlooked factor controlling the structure of telomeric DNA.
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Ten Hagen, K. G., D. M. Gilbert, H. F. Willard i S. N. Cohen. "Replication timing of DNA sequences associated with human centromeres and telomeres". Molecular and Cellular Biology 10, nr 12 (grudzień 1990): 6348–55. http://dx.doi.org/10.1128/mcb.10.12.6348-6355.1990.
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The timing of replication of centromere-associated human alpha satellite DNA from chromosomes X, 17, and 7 as well as of human telomeric sequences was determined by using density-labeling methods and fluorescence-activated cell sorting. Alpha satellite sequences replicated late in S phase; however, the alpha satellite sequences of the three chromosomes studied replicated at slightly different times. Human telomeres were found to replicate throughout most of S phase. These results are consistent with a model in which multiple initiations of replication occur at a characteristic time within the alpha satellite repeats of a particular chromosome, while the replication timing of telomeric sequences is determined by either telomeric origins that can initiate at different times during S phase or by replication origins within the flanking chromosomal DNA sequences.
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Ten Hagen, K. G., D. M. Gilbert, H. F. Willard i S. N. Cohen. "Replication timing of DNA sequences associated with human centromeres and telomeres." Molecular and Cellular Biology 10, nr 12 (grudzień 1990): 6348–55. http://dx.doi.org/10.1128/mcb.10.12.6348.
Pełny tekst źródłaStreszczenie:
The timing of replication of centromere-associated human alpha satellite DNA from chromosomes X, 17, and 7 as well as of human telomeric sequences was determined by using density-labeling methods and fluorescence-activated cell sorting. Alpha satellite sequences replicated late in S phase; however, the alpha satellite sequences of the three chromosomes studied replicated at slightly different times. Human telomeres were found to replicate throughout most of S phase. These results are consistent with a model in which multiple initiations of replication occur at a characteristic time within the alpha satellite repeats of a particular chromosome, while the replication timing of telomeric sequences is determined by either telomeric origins that can initiate at different times during S phase or by replication origins within the flanking chromosomal DNA sequences.