Journal articles: 'Alternative Verlängerung der Telomere'

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Vallejo, Arturo. "Telomere recombination and alternative telomere lengthening mechanisms." Frontiers in Bioscience 18, no. 1 (2013): 1. http://dx.doi.org/10.2741/4084.

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Arnheim, Katharina. "Erhaltungstherapie als Alternative zur Stammzelltransplantation." Onkologische Welt 09, no. 02 (April 2018): 77–78. http://dx.doi.org/10.1055/s-0038-1649313.

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Die Therapie mit dem bispezifischen Antikörper-Konstrukt Blinatumumab wurde in der TOWER-Studie bei rezidivierten und refraktären Patienten mit Philadelphia-Chromosom-negativer (Ph-) B-Vorläufer-ALL (Akute Lymphatische Leukämie) erfolgreich geprüft. Eine neue Auswertung der Studie zeigt jetzt, dass die Erhaltungstherapie mit Blimatumumab nach Erreichen einer kompletten hämatologischen Remission (CHR) für nicht stammzelltransplantierte Patienten aufgrund der Verlängerung des Gesamtüberlebens (OS) vorteilhaft ist.

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Grach, A. A. "Alternative telomere-lengthening mechanisms." Cytology and Genetics 45, no. 2 (April 2011): 121–30. http://dx.doi.org/10.3103/s0095452711020046.

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Dilley, Robert L., Priyanka Verma, Nam Woo Cho, Harrison D. Winters, Anne R. Wondisford, and Roger A. Greenberg. "Break-induced telomere synthesis underlies alternative telomere maintenance." Nature 539, no. 7627 (October 19, 2016): 54–58. http://dx.doi.org/10.1038/nature20099.

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Dilley, Robert L., and Roger A. Greenberg. "ALTernative Telomere Maintenance and Cancer." Trends in Cancer 1, no. 2 (October 2015): 145–56. http://dx.doi.org/10.1016/j.trecan.2015.07.007.

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Royle, N. J., J. Foxon, J. N. Jeyapalan, A. Mendez-Bermudez, C. L. Novo, J. Williams, and V. E. Cotton. "Telomere length maintenance – an ALTernative mechanism." Cytogenetic and Genome Research 122, no. 3-4 (2008): 281–91. http://dx.doi.org/10.1159/000167814.

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Onitake, Yoshiyuki, Eiso Hiyama, Naomi Kamei, Hiroaki Yamaoka, Taijiro Sueda, and Keiko Hiyama. "Telomere biology in neuroblastoma: telomere binding proteins and alternative strengthening of telomeres." Journal of Pediatric Surgery 44, no. 12 (December 2009): 2258–66. http://dx.doi.org/10.1016/j.jpedsurg.2009.07.046.

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Cesare, Anthony J., and Roger R. Reddel. "Telomere uncapping and alternative lengthening of telomeres." Mechanisms of Ageing and Development 129, no. 1-2 (January 2008): 99–108. http://dx.doi.org/10.1016/j.mad.2007.11.006.

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Crunkhorn, Sarah. "An alternative route to targeting telomere elongation." Nature Reviews Drug Discovery 14, no. 3 (February 27, 2015): 165. http://dx.doi.org/10.1038/nrd4558.

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Verma, Priyanka, Robert L. Dilley, Tianpeng Zhang, Melina T. Gyparaki, Yiwen Li, and Roger A. Greenberg. "RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening." Genes & Development 33, no. 3-4 (January 28, 2019): 221–35. http://dx.doi.org/10.1101/gad.319723.118.

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Chen, W., S. M. Chen, Y. Yu, B. K. Xiao, Z. W. Huang, and Z. Z. Tao. "Telomerase inhibition alters telomere maintenance mechanisms in laryngeal squamous carcinoma cells." Journal of Laryngology & Otology 124, no. 7 (April 20, 2010): 778–83. http://dx.doi.org/10.1017/s0022215109992854.

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AbstractBackground and purpose:Telomere length must be maintained throughout cancer cell progression and proliferation. In most tumours, telomerase activity maintains telomere length. Therefore, telomerase is a target for cancer treatments. However, some cancer cells maintain telomere length through an alternative mechanism termed ‘alternative lengthening of telomeres’. To determine how telomerase inhibition relates to the initiation of the alternative lengthening of telomeres pathway, we investigated telomerase activity and telomere maintenance in Hep-2 cells with and without reduced telomerase activity.Materials and methods:We investigated telomerase activity levels in a normal Hep-2 cell line and in residual cells following telomerase inhibition treatment. Additionally, we looked for expression of a marker protein for the alternative lengthening of telomeres mechanism.Results and conclusions:In the residual cells, telomerase activity was eliminated. However, these cells had higher levels of the alternative lengthening of telomeres biomarker, suggesting an alternative mechanism for telomere maintenance following telomerase inhibition. These results could have a major impact on the design of new cancer treatments.

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Udroiu, Ion, and Antonella Sgura. "Alternative Lengthening of Telomeres and Chromatin Status." Genes 11, no. 1 (December 30, 2019): 45. http://dx.doi.org/10.3390/genes11010045.

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Telomere length is maintained by either telomerase, a reverse transcriptase, or alternative lengthening of telomeres (ALT), a mechanism that utilizes homologous recombination (HR) proteins. Since access to DNA for HR enzymes is regulated by the chromatin status, it is expected that telomere elongation is linked to epigenetic modifications. The aim of this review is to elucidate the epigenetic features of ALT-positive cells. In order to do this, it is first necessary to understand the telomeric chromatin peculiarities. So far, the epigenetic nature of telomeres is still controversial: some authors describe them as heterochromatic, while for others, they are euchromatic. Similarly, ALT activity should be characterized by the loss (according to most researchers) or formation (as claimed by a minority) of heterochromatin in telomeres. Besides reviewing the main works in this field and the most recent findings, some hypotheses involving the role of telomere non-canonical sequences and the possible spatial heterogeneity of telomeres are given.

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Zhao, Shuang, Feng Wang, and Lin Liu. "Alternative Lengthening of Telomeres (ALT) in Tumors and Pluripotent Stem Cells." Genes 10, no. 12 (December 10, 2019): 1030. http://dx.doi.org/10.3390/genes10121030.

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A telomere consists of repeated DNA sequences (TTAGGG)n as part of a nucleoprotein structure at the end of the linear chromosome, and their progressive shortening induces DNA damage response (DDR) that triggers cellular senescence. The telomere can be maintained by telomerase activity (TA) in the majority of cancer cells (particularly cancer stem cells) and pluripotent stem cells (PSCs), which exhibit unlimited self-proliferation. However, some cells, such as telomerase-deficient cancer cells, can add telomeric repeats by an alternative lengthening of the telomeres (ALT) pathway, showing telomere length heterogeneity. In this review, we focus on the mechanisms of the ALT pathway and potential clinical implications. We also discuss the characteristics of telomeres in PSCs, thereby shedding light on the therapeutic significance of telomere length regulation in age-related diseases and regenerative medicine.

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Zhang, Huaiying, Rongwei Zhao, Jason Tones, Michel Liu, Robert L. Dilley, David M. Chenoweth, Roger A. Greenberg, and Michael A. Lampson. "Nuclear body phase separation drives telomere clustering in ALT cancer cells." Molecular Biology of the Cell 31, no. 18 (August 15, 2020): 2048–56. http://dx.doi.org/10.1091/mbc.e19-10-0589.

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A chemical dimerization approach is developed to induce phase separation of APB nuclear bodies involved in telomere elongation in alternative lengthening of telomeres (ALT) cancer cells. It reveals that ALT telomere-associated promyelocytic leukemia nuclear body (APB) fusion leads to telomere clustering to provide templates for homology-directed telomere synthesis, an ability that is decoupled from APB function in enriching DNA repair factors.

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Else, Tobias. "Telomeres and telomerase in adrenocortical tissue maintenance, carcinogenesis, and aging." Journal of Molecular Endocrinology 43, no. 4 (May 1, 2009): 131–41. http://dx.doi.org/10.1677/jme-08-0189.

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Telomere dysfunction and telomere maintenance mechanisms contribute to major steps of carcinogenesis. Dysfunctional telomeres lead to the generation of genomic aberrations, such as amplifications and deletions. Telomere maintenance mechanisms, such as telomerase activity and alternative telomere lengthening, provide the basis of malignant cell expansion independent of telomere shortening-induced apoptosis or senescence, ensuring tumor survival. Recent advances highlight the importance of these mechanisms in adrenocortical carcinogenesis. In this review, we will summarize the main models of telomere physiology and their impact on adrenocortical tissue maintenance, aging, and carcinogenesis.

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Sung, Ji-Yong, Hee-Woong Lim, Je-Gun Joung, and Woong-Yang Park. "Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity." Cancers 12, no. 8 (August 7, 2020): 2207. http://dx.doi.org/10.3390/cancers12082207.

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Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism that extends telomeres in cancer cells. It influences tumorigenesis and patient survival. Despite the clinical significance of ALT in tumors, the manner in which ALT is activated and influences prognostic outcomes in distinct cancer types is unclear. In this work, we profiled distinct telomere maintenance mechanisms (TMMs) using 8953 transcriptomes of 31 different cancer types from The Cancer Genome Atlas (TCGA). Our results demonstrated that approximately 29% of cancer types display high ALT activity with low telomerase activity in the telomere-lengthening group. Among the distinct ALT mechanisms, homologous recombination was frequently observed in sarcoma, adrenocortical carcinoma, and kidney chromophobe. Five cancer types showed a significant difference in survival in the presence of high ALT activity. Sarcoma patients with elevated ALT had unfavorable risks (p < 0.038) coupled with a high expression of TOP2A, suggesting this as a potential drug target. On the contrary, glioblastoma patients had favorable risks (p < 0.02), and showed low levels of antigen-presenting cells. Together, our analyses highlight cancer type-dependent TMM activities and ALT-associated genes as potential therapeutic targets.

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Kargaran, Parisa K., Hemad Yasaei, Sara Anjomani-Virmouni, Giovanna Mangiapane, and Predrag Slijepcevic. "Analysis of alternative lengthening of telomere markers inBRCA1defective cells." Genes, Chromosomes and Cancer 55, no. 11 (July 26, 2016): 864–76. http://dx.doi.org/10.1002/gcc.22386.

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Kretzschmar, Kretzschmar. "Konsolidierung verlängert progressionsfreies Überleben um fast 3 Jahre: Neue Daten zur Radioimmuntherapie mit Zevalin®." Onkologische Welt 02, no. 03 (2011): 118. http://dx.doi.org/10.1055/s-0038-1631249.

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Die Konsolidierungstherapie mit 90Y-Ibritumumab-Tiuxetan (Zevalin®) führt bei Patienten mit fortgeschrittenem follikulären Lymphom zu einer Verlängerung des progressionsfreien Überlebens (PFS) um 34 Monate im Vergleich zur Kontrollgruppe. Dies zeigt eine neue Auswertung nach 5,5 Jahren Follow-Up. Eine Radioimmuntherapie (RIT) mit dem Radioliganden könnte darüber hinaus eine effektive und gut verträgliche Alternative zur First-line-Chemotherapie werden. In einer auf der vergangenen ASH-Jahrestagung vorgestellten Phase-II-Studie wurden ähnlich hohe Remissionsraten wie mit einer Standard-Chemotherapie erreicht.

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Jiang, Wei-Qin, Ze-Huai Zhong, Jeremy D. Henson, Axel A. Neumann, Andy C. M. Chang, and Roger R. Reddel. "Suppression of Alternative Lengthening of Telomeres by Sp100-Mediated Sequestration of the MRE11/RAD50/NBS1 Complex." Molecular and Cellular Biology 25, no. 7 (April 1, 2005): 2708–21. http://dx.doi.org/10.1128/mcb.25.7.2708-2721.2005.

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ABSTRACT Approximately 10% of cancers overall use alternative lengthening of telomeres (ALT) instead of telomerase to prevent telomere shortening, and ALT is especially common in astrocytomas and various types of sarcomas. The hallmarks of ALT in telomerase-negative cancer cells include a unique pattern of telomere length heterogeneity, rapid changes in individual telomere lengths, and the presence of ALT-associated promyelocytic leukemia bodies (APBs) containing telomeric DNA and proteins involved in telomere binding, DNA replication, and recombination. The ALT mechanism appears to involve recombination-mediated DNA replication, but the molecular details are largely unknown. In telomerase-null Saccharomyces cerevisiae, an analogous survivor mechanism is dependent on the RAD50 gene. We demonstrate here that overexpression of Sp100, a constituent of promyelocytic leukemia nuclear bodies, sequestered the MRE11, RAD50, and NBS1 recombination proteins away from APBs. This resulted in repression of the ALT mechanism, as evidenced by progressive telomere shortening at 121 bp per population doubling, a rate within the range found in telomerase-negative normal cells, suppression of rapid telomere length changes, and suppression of APB formation. Spontaneously generated C-terminally truncated Sp100 that did not sequester the MRE11, RAD50, and NBS1 proteins failed to inhibit ALT. These findings identify for the first time proteins that are required for the ALT mechanism.

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Damle, Rajendra N., Taraneh Banapour, Cristina Sison, Steven L. Allen, Kanti R. Rai, and Nicholas Chiorazzi. "Evidence for Alternative Lengthening of Telomeres in Chronic Lymphocytic Leukemia Patients." Blood 106, no. 11 (November 16, 2005): 1179. http://dx.doi.org/10.1182/blood.v106.11.1179.1179.

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Abstract Telomere shortening is a consequence of repetitive clonal replication and leads to clonal deletion unless DNA extension and repair occur. All tumors must circumvent this problem by up-regulating mechanisms that lead to chromosomal lengthening. Two mechanisms have been identified that maintain chromosome ends- telomerase that does so by reverse transcription and alternative lengthening of telomeres (ALT) that occurs by homologous recombination. The latter function is characterized by the presence of promyelocytic leukemia protein-associated nuclear bodies (PML-NBs) and the presence of PML-NB is used to mark cells that use this process. B cell Chronic lymphocytic leukemia (B-CLL) cells with unmutated Ig V genes have shorter mean telomere lengths compared with those exhibiting mutated Ig V genes. In addition, cells with unmutated Ig V genes demonstrate more telomerase activity than their mutated counterparts. The mutated cases show long and heterogeneously elongated telomeres in spite of the absence, in most cases, of detectable telomerase activity. Therefore we determined whether the ALT pathway plays a role in telomere maintenance in B-CLL, using a monoclonal anti-PML antibody and a flow-cytometric assay for assessment of PML protein. Telomerase-expressing Jurkat T cells and murine fibroblasts-L cells served as negative controls for PML staining, whereas the ALT positive Osteosarcoma cell line U2-OS served as a positive control. In a cohort of 20 B-CLL cases, PML protein was detected in all cases regardless of Ig V mutation status. In addition, a similar percentage of cells within the clones contained PML (10 - 90% of the members of unmutated clones and 11–96% of mutated clones), whereas peripheral blood B cells from 6/6 elderly normal donors did not show any PML staining. PML expression was compared with telomere length and telomerase activity in the same cases. The percentage of cells showing PML expression inversely correlated with telomerase activity (r= −0.58; p=0.029). Although in most published reports telomere maintenance by ALT occurs in the absence of telomerase activity, we found ALT (as suggested by PML positive cells) in cells with telomerase activity (detected by the standard TRAP assay). Thus, B-CLL cases can express PML bodies and some B-CLL cells can contain both PML-NB and express telomerase activity. These findings suggest that B-CLL cells can use two distinct mechanisms to assure telomere maintenance and perpetuate clonal survival and expansion.

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Recagni, Marta, Joanna Bidzinska, Nadia Zaffaroni, and Marco Folini. "The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications." Cancers 12, no. 4 (April 11, 2020): 949. http://dx.doi.org/10.3390/cancers12040949.

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Telomere maintenance mechanisms (i.e., telomerase activity (TA) and the alternative lengthening of telomere (ALT) mechanism) contribute to tumorigenesis by providing unlimited proliferative capacity to cancer cells. Although the role of either telomere maintenance mechanisms seems to be equivalent in providing a limitless proliferative ability to tumor cells, the contribution of TA and ALT to the clinical outcome of patients may differ prominently. In addition, several strategies have been developed to interfere with TA in cancer, including Imetelstat that has been the first telomerase inhibitor tested in clinical trials. Conversely, the limited information available on the molecular underpinnings of ALT has hindered thus far the development of genuine ALT-targeting agents. Moreover, whether anti-telomerase therapies may be hampered or not by possible adaptive responses is still debatable. Nonetheless, it is plausible hypothesizing that treatment with telomerase inhibitors may exert selective pressure for the emergence of cancer cells that become resistant to treatment by activating the ALT mechanism. This notion, together with the evidence that both telomere maintenance mechanisms may coexist within the same tumor and may distinctly impinge on patients’ outcomes, suggests that ALT may exert an unexpected role in tumor biology that still needs to be fully elucidated.

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de Lange, Titia. "Shelterin-Mediated Telomere Protection." Annual Review of Genetics 52, no. 1 (November 23, 2018): 223–47. http://dx.doi.org/10.1146/annurev-genet-032918-021921.

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For more than a decade, it has been known that mammalian cells use shelterin to protect chromosome ends. Much progress has been made on the mechanism by which shelterin prevents telomeres from inadvertently activating DNA damage signaling and double-strand break (DSB) repair pathways. Shelterin averts activation of three DNA damage response enzymes [the ataxia-telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases and poly(ADP-ribose) polymerase 1 (PARP1)], blocks three DSB repair pathways [classical nonhomologous end joining (c-NHEJ), alternative (alt)-NHEJ, and homology-directed repair (HDR)], and prevents hyper-resection at telomeres. For several of these functions, mechanistic insights have emerged. In addition, much has been learned about how shelterin maintains the telomeric 3′ overhang, forms and protects the t-loop structure, and promotes replication through telomeres. These studies revealed that shelterin is compartmentalized, with individual subunits dedicated to distinct aspects of the end-protection problem. This review focuses on the current knowledge of shelterin-mediated telomere protection, highlights differences between human and mouse shelterin, and discusses some of the questions that remain.

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Lau, Loretta M. S., Rebecca A. Dagg, Jeremy D. Henson, Amy Y. M. Au, Janice A. Royds, and Roger R. Reddel. "Detection of alternative lengthening of telomeres by telomere quantitative PCR." Nucleic Acids Research 41, no. 2 (August 24, 2012): e34-e34. http://dx.doi.org/10.1093/nar/gks781.

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Lundblad, Victoria, and Elizabeth H. Blackburn. "An alternative pathway for yeast telomere maintenance rescues est1− senescence." Cell 73, no. 2 (April 1993): 347–60. http://dx.doi.org/10.1016/0092-8674(93)90234-h.

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Kockler, Zachary W., Josep M. Comeron, and Anna Malkova. "A unified alternative telomere-lengthening pathway in yeast survivor cells." Molecular Cell 81, no. 8 (April 2021): 1816–29. http://dx.doi.org/10.1016/j.molcel.2021.02.004.

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Kishtagari, Ashwin, and Justin Watts. "Biological and clinical implications of telomere dysfunction in myeloid malignancies." Therapeutic Advances in Hematology 8, no. 11 (October 6, 2017): 317–26. http://dx.doi.org/10.1177/2040620717731549.

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Telomeres at the ends of linear chromosomes protect the genome. Telomeres shorten with each round of cell division, placing a finite limit on cell growth. Telomere attrition is associated with cell senescence and apoptosis. Telomerase, a specialized ribonucleoprotein complex, maintains telomeres homeostasis through repeat addition of telomere sequences to the 3′ telomeric overhang. Telomere biology is closely related to cancer and normal aging. Upregulation of telomerase or activation of the alternative pathway of telomere lengthening is a hallmark of cancer cells, making telomerase an attractive target for cancer therapeutics. In this review, we will discuss telomere biology and the prognostic implications of telomere length in acute myeloid leukemia, and review exciting new investigational approaches using telomerase inhibitors in acute myeloid leukemia and other myeloid malignancies.

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Birzu, C., A. Hillairet, M. Giry, N. Grandin, P. Verrelle, K. Mokhtari, Y. Marie, et al. "OS9.7 Telomere length, TERTp mutation and ALT status in adult diffuse gliomas." Neuro-Oncology 21, Supplement_3 (August 2019): iii19—iii20. http://dx.doi.org/10.1093/neuonc/noz126.065.

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Abstract BACKGROUND The current classification of adult diffuse gliomas integrates two alternative telomere maintenance mechanisms: reactivation of telomerase activity by TERT promoter (TERTp) mutations or ATRX mutations associated with alternative length telomere (ALT). We investigated here the relation between these two mechanisms, telomere length, and outcome in a large series of diffuse gliomas. MATERIAL AND METHODS We performed C-circle assay (CCA) to determine ALT status, determined telomere length in tumor (RTLt) and leukocyte (RTLl) in a cohort of 354 adult diffuse gliomas, and sequenced ATRX gene. We calculated an age-adjusted telomere score considering tumor and leukocyte (blood) telomere length and corrected by age. This score was used in univariate and multivariate survival analyses to evaluate the potential impact of telomere length on the prognosis of gliomas. We used the TCGA LGG-GBM dataset to validate our findings in an independent cohort. RESULTS RTLl and RTLt were associated with ATRX mutation and ALT phenotype, and negatively associated with age and TERTp mutations. ATRX mutations (found in 52% (64/123) of samples) were mostly transitions (C>T or T>C), and were associated with ALT phenotype. None of 1p/19q co-deleted oligodendrogliomas harbored an ALT phenotype. No patients with TERTp mutations had ALT phenotype except for a very small subgroup of patients (3/87, 3.4%) suggesting that multiple ways of telomere maintenance, may co-exist in a single tumor, probably expressed in different clones. Telomere age-adjusted score was independently associated with better outcome (HR= 0.73 [95% CI 0.56–0.97], p-value 0.03 adjusted for age, TERTp mutation, IDH mutation, 1p/19q co-deletion and WHO grade). These results were validated using the LGG-GBM TCGA dataset. CONCLUSION We unravel the relation between RTLl and RTLt, TERTp mutation and ALT phenotype and describe a novel telomere age-adjusted score independently associated with better prognosis in adult diffuse gliomas.

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Xu, Mafei, Jun Qin, Leiming Wang, Hui-Ju Lee, Chung-Yang Kao, Dan Liu, Zhou Songyang, Junjie Chen, Ming-Jer Tsai, and Sophia Y. Tsai. "Nuclear receptors regulate alternative lengthening of telomeres through a novel noncanonical FANCD2 pathway." Science Advances 5, no. 10 (October 2019): eaax6366. http://dx.doi.org/10.1126/sciadv.aax6366.

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Alternative lengthening of telomeres (ALT) is known to use homologous recombination (HR) to replicate telomeric DNA in a telomerase-independent manner. However, the detailed process remains largely undefined. It was reported that nuclear receptors COUP-TFII and TR4 are recruited to the enriched GGGTCA variant repeats embedded within ALT telomeres, implicating nuclear receptors in regulating ALT activity. Here, we identified a function of nuclear receptors in ALT telomere maintenance that involves a direct interaction between COUP-TFII/TR4 and FANCD2, the key protein in the Fanconi anemia (FA) DNA repair pathway. The COUP-TFII/TR4-FANCD2 complex actively induces the DNA damage response by recruiting endonuclease MUS81 and promoting the loading of the PCNA-POLD3 replication complex in ALT telomeres. Furthermore, the COUP-TFII/TR4-mediated ALT telomere pathway does not require the FA core complex or the monoubiquitylation of FANCD2, key steps in the canonical FA pathway. Thus, our findings reveal that COUP-TFII/TR4 regulates ALT telomere maintenance through a novel noncanonical FANCD2 pathway.

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Robinson, Nathaniel J., Masaru Miyagi, Jessica A. Scarborough, Jacob G. Scott, Derek J. Taylor, and William P. Schiemann. "SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-κB and Notch signaling." Science Signaling 14, no. 689 (June 29, 2021): eabe9613. http://dx.doi.org/10.1126/scisignal.abe9613.

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The maintenance of telomere length supports repetitive cell division and therefore plays a central role in cancer development and progression. Telomeres are extended by either the enzyme telomerase or the alternative lengthening of telomeres (ALT) pathway. Here, we found that the telomere-associated protein SLX4IP dictates telomere proteome composition by recruiting and activating the E3 SUMO ligase PIAS1 to the SLX4 complex. PIAS1 SUMOylated the telomere-binding protein RAP1, which disrupted its interaction with the telomere-binding protein TRF2 and facilitated its nucleocytoplasmic shuttling. In the cytosol, RAP1 bound to IκB kinase (IKK), resulting in activation of the transcription factor NF-κB and its induction of Jagged-1 expression, which promoted Notch signaling and the institution of ALT. This axis could be targeted therapeutically in ALT-driven cancers and in tumor cells that develop resistance to antitelomerase therapies. Our results illuminate the mechanisms underlying SLX4IP-dependent telomere plasticity and demonstrate the role of telomere proteins in directly coordinating intracellular signaling and telomere maintenance dynamics.

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Baumert, Steinauer, and Lütolf. "Treatment of brain metastases." Therapeutische Umschau 56, no. 6 (June 1, 1999): 338–41. http://dx.doi.org/10.1024/0040-5930.56.6.338.

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ZNS-Metastasen des malignen Melanoms unterscheiden sich in ihrer Therapie aus radio-onkologischer Sicht nicht wesentlich von der Behandlung der übrigen Hirnmetastasen. ZNS-Metastasen sind im Zusammenhang mit der Grunderkrankung einer der schlechtesten prognostischen Faktoren. Für die in der Mehrheit multipel auftretenden ZNS-Metastasen ist in der Regel die Ganzhirnbestrahlung die Therapie der Wahl. In der Behandlung der prognostisch günstigeren singulären ZNS-Metastasen ist die operative Resektion kombiniert mit einer Ganzhirnbestrahlung die bevorzugte Therapie. Das Behandlungsziel ist sowohl bei singulären, als auch bei multiplen Hirnmetastasen primär palliativ, aber gerade aus diesem Grunde erscheint es wichtig, verschiedene Behandlungsstrategien wie Operation, Ganzhirnbestrahlung, Radiochirurgie oder deren Kombination sorgfältig gegeneinander abzuwägen und gezielt einzusetzen. Beim Vergleich unterschiedlicher Behandlungsmodalitäten sollten nicht nur eine Verlängerung der Überlebenszeit oder eine Verlängerung des rezidivfreien Intervalles, sondern ebenso die Lebensqualität in den Überlegungen berücksichtigt werden. Um die Ergebnisse verschiedener Therapieformen vergleichen zu können, sind prospektiv randomisierte Studien notwendig. Eine definitive Aussage über die Einordnung der Radiochirurgie als Standardmethode in ein Gesamtkonzept kann bis zum Vorliegen guter klinischer Studien nicht abschließend beurteilt werden. Für ausgewählte Patienten in gutem Allgemeinzustand mit kontrollierter Grunderkrankung, bei operativ schwer zugänglichen Läsionen, bei rezidivierten Metastasen nach vorhergehender konventioneller Therapie, erscheint die Radiochirurgie als gute therapeutische Alternative.

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Subecz, Chloé, Jian-Sheng Sun, and Lauréline Roger. "Effect of DNA repair inhibitor AsiDNA on the incidence of telomere fusion in crisis." Human Molecular Genetics 30, no. 3-4 (January 22, 2021): 172–81. http://dx.doi.org/10.1093/hmg/ddab008.

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Abstract Telomere fusions lead to a state of genomic instability, and are thought to drive clonal evolution and tumorigenesis. Telomere fusions occur via both Classical and Alternative Non-Homologous End Joining repair pathways. AsiDNA is a DNA repair inhibitor that acts by mimicking a DNA double strand break (DSB) and hijacking the recruitment of proteins involved in various DNA repair pathways. In this study, we investigated whether the inhibition of DSB-repair pathways by AsiDNA could prevent telomere fusions during crisis. The present study showed that AsiDNA decreased the frequency of telomere fusions without affecting the rate of telomere erosion. Further, it indicated that AsiDNA does not impact the choice of the repair pathway used for the fusion of short dysfunctional telomeres. AsiDNA is thought to prevent short telomeres from fusing by inhibiting DNA repair. An alternative, non-mutually exclusive possibility is that cells harbouring fusions preferentially die in the presence of AsiDNA, thus resulting in a reduction in fusion frequency. This important work could open the way for investigating the use of AsiDNA in the treatment of tumours that have short dysfunctional telomeres and/or are experiencing genomic instability.

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Siddiqa, Aisha, David Cavazos, Jeffery Chavez, Linda Long, and Robert A. Marciniak. "Modulation of Telomeres in Alternative Lengthening of Telomeres Type I Like Human Cells by the Expression of Werner Protein and Telomerase." Journal of Oncology 2012 (2012): 1–11. http://dx.doi.org/10.1155/2012/806382.

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The alternative lengthening of telomeres (ALT) is a recombination-based mechanism of telomere maintenance activated in 5–20% of human cancers. InSaccharomyces cerevisiae, survivors that arise after inactivation of telomerase can be classified as type I or type II ALT. In type I, telomeres have a tandem array structure, with each subunit consisting of a subtelomeric Y′ element and short telomere sequence. Telomeres in type II have only long telomere repeats and require Sgs1, theS. cerevisiaeRecQ family helicase. We previously described the first human ALT cell line, AG11395, that has a telomere structure similar to type I ALT yeast cells. This cell line lacks the activity of the Werner syndrome protein, a human RecQ helicase. The telomeres in this cell line consist of tandem repeats containing SV40 DNA, including the origin of replication, and telomere sequence. We investigated the role of the SV40 origin of replication and the effects of Werner protein and telomerase on telomere structure and maintenance in AG11395 cells. We report that the expression of Werner protein facilitates the transition in human cells of ALT type I like telomeres to type II like telomeres in some aspects. These findings have implications for the diagnosis and treatment of cancer.

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Cohn, Marita, Ahu Karademir Andersson, Raquel Quintilla Mateo, and Mirja Carlsson Möller. "Alternative Lengthening of Telomeres in the Budding Yeast Naumovozyma castellii." G3: Genes|Genomes|Genetics 9, no. 10 (August 19, 2019): 3345–58. http://dx.doi.org/10.1534/g3.119.400428.

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The enzyme telomerase ensures the integrity of linear chromosomes by maintaining telomere length. As a hallmark of cancer, cell immortalization and unlimited proliferation is gained by reactivation of telomerase. However, a significant fraction of cancer cells instead uses alternative telomere lengthening mechanisms to ensure telomere function, collectively known as Alternative Lengthening of Telomeres (ALT). Although the budding yeast Naumovozyma castellii (Saccharomyces castellii) has a proficient telomerase activity, we demonstrate here that telomeres in N. castellii are efficiently maintained by a novel ALT mechanism after telomerase knockout. Remarkably, telomerase-negative cells proliferate indefinitely without any major growth crisis and display wild-type colony morphology. Moreover, ALT cells maintain linear chromosomes and preserve a wild-type DNA organization at the chromosome termini, including a short stretch of terminal telomeric sequence. Notably, ALT telomeres are elongated by the addition of ∼275 bp repeats containing a short telomeric sequence and the subtelomeric DNA located just internally (TelKO element). Although telomeres may be elongated by several TelKO repeats, no dramatic genome-wide amplification occurs, thus indicating that the repeat addition may be regulated. Intriguingly, a short interstitial telomeric sequence (ITS) functions as the initiation point for the addition of the TelKO element. This implies that N. castellii telomeres are structurally predisposed to efficiently switch to the ALT mechanism as a response to telomerase dysfunction.

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da Silva, Guilherme G., Karollyne S. Morais, Daniel S. Arcanjo, and Diêgo M. de Oliveira. "Clinical Relevance of Alternative Lengthening of Telomeres in Cancer." Current Topics in Medicinal Chemistry 20, no. 6 (April 13, 2020): 485–97. http://dx.doi.org/10.2174/1568026620666200110112854.

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The alternative lengthening of telomere (ALT) is a pathway responsible for cell immortalization in some kinds of tumors. Since the first description of ALT is relatively recent in the oncology field, its mechanism remains elusive, but recent works address ALT-related proteins or cellular structures as potential druggable targets for more specific and efficient antitumor therapies. Moreover, some new generation compounds for antitelomerase therapy in cancer were able to provoke acquisition of ALT phenotype in treated tumors, enhancing the importance of studies on this alternative lengthening of the telomere. However, ALT has been implicated in different – sometimes opposite – outcomes, according to the tumor type studied. Then, in order to design and develop new drugs for ALT+ cancer in an effective way, it is crucial to understand its clinical implications. In this review, we gathered works published in the last two decades to highlight the clinical relevance of ALT on oncology.

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Cheng, C., L. Shtessel, M. M. Brady, and S. Ahmed. "Caenorhabditis elegans POT-2 telomere protein represses a mode of alternative lengthening of telomeres with normal telomere lengths." Proceedings of the National Academy of Sciences 109, no. 20 (April 30, 2012): 7805–10. http://dx.doi.org/10.1073/pnas.1119191109.

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Stoklosa, Tomasz, Anna Deregowska, Katarzyna Pruszczyk, Iwona Solarska, Marcin M. Machnicki, Jagoda Adamczyk, Ilona Seferynska, Anna Lewinska, and Maciej Wnuk. "Role of Shelterin Complex and Alternative Telomere Lengthening in Genomic Instability and Disease Progression in Chronic Myeloid Leukemia." Blood 128, no. 22 (December 2, 2016): 1880. http://dx.doi.org/10.1182/blood.v128.22.1880.1880.

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Abstract Genomic instability has many sources, among others, shortening of telomeres, nucleoprotein complexes located at the ends of chromosomes. Tumor cells have aberrant mechanisms of telomere maintenance: their telomeres are shortened, no longer preventing chromosome end-to-end fusion and recombination, but frequently not short enough to lead to cell senescence. Both telomerase and shelterin complexes are involved in telomere homeostasis. Reduction in the telomere length is considered as one of the features of chronic myeloid leukemia (CML) similar to other human malignancies and telomere shortening is correlated with disease progression from the chronic phase (CML-CP) to the blastic phase (CML-BP)1. However, recent report shows that shorter telomeres can actually be detected in patients who discontinued imatinib and are in treatment-free remission as compared to those who relapsed2. Therefore, there is no agreement on the telomere length dynamics in CML evolution. Moreover, the precise role of telomere-associated proteins, including shelterin complex in BCR-ABL1-mediated genomic instability in CML progression and resistance to TKIs, is not fully elucidated. Initially, we confirmed that the telomere shortening was positively correlated with CML progression (CML-BP in comparison to CML-CP). However, in CD34+ samples from CML-CP TKI-resistant patients in comparison to CML-CP patients, an increase in telomere length was observed. This suggests that shortening of telomeres in CML progression may have a biphasic scenario. This can be explained by alternative telomere lengthening (ALT) mechanisms, since no significant changes in the expression of subunits of the telomerase complex and its enzymatic activity were observed at different phases of the disease; enzymatic activity of telomerase was measured immunoenzymatically, while length of telomeres was determined by Southern blotting. Then we decided to analyze possible involvement of shelterin complex and of ALT mechanisms in CML progression. Importantly, expression of the three members of the shelterin complex, Protection Of Telomeres 1 (POT1), Repressor Activator Protein 1 (RAP1) and Tankyrase 1 (TNKS1) was significantly upregulated in CML-BP (10 samples) as compared to CML-CP (15 samples) and was also positively correlated with BCR-ABL1 expression. Moreover, as determined by TKI treatment of CD34+ CML-BP primary cells, expression of POT1 was BCR-ABL1-dependent. No significant changes were observed in the expression of other members of the shelterin complex, namely TINT1-PTOP-PIP1 (TPP1), TRF1 interactor 2 (TIN2) and Tankyrase 2 (TNKS2). Also telomere repeat-binding factor 1 and 2 (TRF1 and TRF2), which are responsible for anchoring shelterin complex to the double stranded telomeric repeats remain stable in the course of the disease. Expression of subunits of telomerase and shelterin complexes was examined by RT-qPCR and Western blotting. This was confirmed in K562 and K562 imatinib-resistant cell line model. Somatic mutations in POT1 have been recently described in human tumors including chronic lymphocytic leukemia (CLL). In CLL, mutations in POT1 affect telomere stability and are associated with shorter survival in patients receiving chemotherapy as a frontline treatment. We have screened our NGS data from targeted sequencing in a cohort of patients who progressed to CML-BP (paired CP and BP samples, n=10 and BP samples, n=9) but we did not detect any somatic mutations in POT1. This is in accordance with our data on POT1 upregulated expression and suggests that dysregulation of shelterin complex during progression of CML differs significantly from CLL. In conclusion, we present the first comprehensive analysis of the expression of all members of the shelterin complex in the course of CML. We postulate that abnormal expression of selected members such as POT1, RAP1 and TNKS1 may be responsible for the aberrant telomere maintenance mechanisms in CML cells and may play an important role in genomic instability associated with CML progression. References: 1. Brummendorf TH, et al. Blood 2000; 95:1883-1890. 2. Caocci et al. Journal of Hematology & Oncology 2016; 9:63; Disclosures Seferynska: Novartis: Consultancy, Honoraria.

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Hsu, Joseph K., Tao Lin, and Robert Y. L. Tsai. "Nucleostemin prevents telomere damage by promoting PML-IV recruitment to SUMOylated TRF1." Journal of Cell Biology 197, no. 5 (May 28, 2012): 613–24. http://dx.doi.org/10.1083/jcb.201109038.

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Continuously dividing cells must be protected from telomeric and nontelomeric DNA damage in order to maintain their proliferative potential. Here, we report a novel telomere-protecting mechanism regulated by nucleostemin (NS). NS depletion increased the number of telomere damage foci in both telomerase-active (TA+) and alternative lengthening of telomere (ALT) cells and decreased the percentage of damaged telomeres associated with ALT-associated PML bodies (APB) and the number of APB in ALT cells. Mechanistically, NS could promote the recruitment of PML-IV to SUMOylated TRF1 in TA+ and ALT cells. This event was stimulated by DNA damage. Supporting the importance of NS and PML-IV in telomere protection, we demonstrate that loss of NS or PML-IV increased the frequency of telomere damage and aberration, reduced telomeric length, and perturbed the TRF2ΔBΔM-induced telomeric recruitment of RAD51. Conversely, overexpression of either NS or PML-IV protected ALT and TA+ cells from telomere damage. This work reveals a novel mechanism in telomere protection.

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Tomita, Kazunori, Akira Matsuura, Thomas Caspari, Antony M. Carr, Yufuko Akamatsu, Hiroshi Iwasaki, Ken-ichi Mizuno, et al. "Competition between the Rad50 Complex and the Ku Heterodimer Reveals a Role for Exo1 in Processing Double-Strand Breaks but Not Telomeres." Molecular and Cellular Biology 23, no. 15 (August 1, 2003): 5186–97. http://dx.doi.org/10.1128/mcb.23.15.5186-5197.2003.

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ABSTRACT The Mre11-Rad50-Nbs1(Xrs2) complex and the Ku70-Ku80 heterodimer are thought to compete with each other for binding to DNA ends. To investigate the mechanism underlying this competition, we analyzed both DNA damage sensitivity and telomere overhangs in Schizosaccharomyces pombe rad50-d, rad50-d pku70-d, rad50-d exo1-d, and pku70-d rad50-d exo1-d cells. We found that rad50 exo1 double mutants are more methyl methanesulfonate (MMS) sensitive than the respective single mutants. The MMS sensitivity of rad50-d cells was suppressed by concomitant deletion of pku70+ . However, the MMS sensitivity of the rad50 exo1 double mutant was not suppressed by the deletion of pku70+ . The G-rich overhang at telomere ends in taz1-d cells disappeared upon deletion of rad50+ , but the overhang reappeared following concomitant deletion of pku70+ . Our data suggest that the Rad50 complex can process DSB ends and telomere ends in the presence of the Ku heterodimer. However, the Ku heterodimer inhibits processing of DSB ends and telomere ends by alternative nucleases in the absence of the Rad50-Rad32 protein complex. While we have identified Exo1 as the alternative nuclease targeting DNA break sites, the identity of the nuclease acting on the telomere ends remains elusive.

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Brault, Marie Eve, and Chantal Autexier. "Telomeric recombination induced by dysfunctional telomeres." Molecular Biology of the Cell 22, no. 2 (January 15, 2011): 179–88. http://dx.doi.org/10.1091/mbc.e10-02-0173.

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Telomere maintenance is essential for cellular immortality, and most cancer cells maintain their telomeres through the enzyme telomerase. Telomeres and telomerase represent promising anticancer targets. However, 15% of cancer cells maintain their telomeres through alternative recombination-based mechanisms, and previous analyses showed that recombination-based telomere maintenance can be activated after telomerase inhibition. We determined whether telomeric recombination can also be promoted by telomere dysfunction. We report for the first time that telomeric recombination can be induced in human telomerase-positive cancer cells with dysfunctional telomeres.

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Miller, Kurt. "Abirateron plus Prednison beim neu diagnostizierten Hochrisiko-metastasierten hormonsensitiven Prostatakarzinom (mHSPC)." Aktuelle Urologie 50, no. 06 (March 27, 2019): 625–28. http://dx.doi.org/10.1055/a-0852-3405.

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ZusammenfassungDie Ergebnisse der beiden Studien LATITUDE 1 und STAMPEDE 2 zur Kombinationstherapie von Abirateron plus Prednison (Abirateron/P) mit konventioneller ADT haben eine praxisverändernde Alternative zur kombinierten Hormon-Chemotherapie mit ADT plus Docetaxel in der Erstlinientherapie des neu diagnostizierten Hochrisiko-metastasierten hormonsensitiven Prostatakarzinoms (mHSPC) aufgezeigt. In beiden Studien führte Abirateron/P zu einer deutlichen Verlängerung des progressionsfreien und Gesamtüberlebens. Ob Abirateron/P plus ADT als neuer Goldstandard beim neu diagnostizierten Hochrisiko-mHSPC anzusehen ist, kann derzeit nicht sicher beurteilt werden, da direkte Vergleichsstudien noch fehlen. Die vorliegenden indirekten Daten zeigen aber, dass Abirateron/P eine mindestens vergleichbare, wenn nicht sogar etwas höhere Effektivität aufweist, bei einer insgesamt besseren Verträglichkeit.

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Sommer, Aurore, and Nicola J. Royle. "ALT: A Multi-Faceted Phenomenon." Genes 11, no. 2 (January 27, 2020): 133. http://dx.doi.org/10.3390/genes11020133.

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One of the hallmarks of cancer cells is their indefinite replicative potential, made possible by the activation of a telomere maintenance mechanism (TMM). The majority of cancers reactivate the reverse transcriptase, telomerase, to maintain their telomere length but a minority (10% to 15%) utilize an alternative lengthening of telomeres (ALT) pathway. Here, we review the phenotypes and molecular markers specific to ALT, and investigate the significance of telomere mutations and sequence variation in ALT cell lines. We also look at the recent advancements in understanding the different mechanisms behind ALT telomere elongation and finally, the progress made in identifying potential ALT-targeted therapies, including those already in use for the treatment of both hematological and solid tumors.

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Kim, Jeongkyu, Chongkui Sun, Andy D. Tran, Pei-Ju Chin, Penelope D. Ruiz, Kun Wang, Richard J. Gibbons, Matthew J. Gamble, Yie Liu, and Philipp Oberdoerffer. "The macroH2A1.2 histone variant links ATRX loss to alternative telomere lengthening." Nature Structural & Molecular Biology 26, no. 3 (March 2019): 213–19. http://dx.doi.org/10.1038/s41594-019-0192-3.

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Tsai, Yun-Luen, Shun-Fu Tseng, Shih-Husan Chang, Chuan-Chuan Lin, and Shu-Chun Teng. "Involvement of Replicative Polymerases, Tel1p, Mec1p, Cdc13p, and the Ku Complex in Telomere-Telomere Recombination." Molecular and Cellular Biology 22, no. 16 (August 15, 2002): 5679–87. http://dx.doi.org/10.1128/mcb.22.16.5679-5687.2002.

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ABSTRACT Telomere maintenance is required for chromosome stability, and telomeres are typically replicated by the action of the reverse transcriptase telomerase. In both tumor and yeast cells that lack telomerase, telomeres are maintained by an alternative recombination mechanism. Genetic studies have led to the identification of DNA polymerases, cell cycle checkpoint proteins, and telomere binding proteins involved in the telomerase pathway. However, how these proteins affect telomere-telomere recombination has not been identified to date. Using an assay to trace the in vivo recombinational products throughout the course of survivor development, we show here that three major replicative polymerases, α, δ, and ε, play roles in telomere-telomere recombination and that each causes different effects and phenotypes when they as well as the telomerase are defective. Polymerase δ appears to be the main activity for telomere extension, since neither type I nor type II survivors arising via telomere-telomere recombination were seen in its absence. The frequency of type I versus type II is altered in the polymerase α and ε mutants relative to the wild type. Each prefers to develop a particular type of survivor. Moreover, type II recombination is mediated by the cell cycle checkpoint proteins Tel1 and Mec1, and telomere-telomere recombination is regulated by telomere binding protein Cdc13 and the Ku complex. Together, our results suggest that coordination between DNA replication machinery, DNA damage signaling, DNA recombination machinery, and the telomere protein-DNA complex allows telomere recombination to repair telomeric ends in the absence of telomerase.

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Iyer, Shilpa, Ashley D. Chadha, and Michael J. McEachern. "A Mutation in the STN1 Gene Triggers an Alternative Lengthening of Telomere-Like Runaway Recombinational Telomere Elongation and Rapid Deletion in Yeast." Molecular and Cellular Biology 25, no. 18 (September 15, 2005): 8064–73. http://dx.doi.org/10.1128/mcb.25.18.8064-8073.2005.

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ABSTRACT Some human cancer cells achieve immortalization by using a recombinational mechanism termed ALT (alternative lengthening of telomeres). A characteristic feature of ALT cells is the presence of extremely long and heterogeneous telomeres. The molecular mechanism triggering and maintaining this pathway is currently unknown. In Kluyveromyces lactis, we have identified a novel allele of the STN1 gene that produces a runaway ALT-like telomeric phenotype by recombination despite the presence of an active telomerase pathway. Additionally, stn1-M1 cells are synthetically lethal in combination with rad52 and display chronic growth and telomere capping defects including extensive 3′ single-stranded telomere DNA and highly elevated subtelomere gene conversion. Strikingly, stn1-M1 cells undergo a very high rate of telomere rapid deletion (TRD) upon reintroduction of STN1. Our results suggest that the protein encoded by STN1, which protects the terminal 3′ telomere DNA, can regulate both ALT and TRD.

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Yuan, Xiaotian, Mingkai Dai, and Dawei Xu. "Telomere-related Markers for Cancer." Current Topics in Medicinal Chemistry 20, no. 6 (April 13, 2020): 410–32. http://dx.doi.org/10.2174/1568026620666200106145340.

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Telomeres are structurally nucleoprotein complexes at termini of linear chromosomes and essential to chromosome stability/integrity. In normal human cells, telomere length erodes progressively with each round of cell divisions, which serves as an important barrier to uncontrolled proliferation and malignant transformation. In sharp contrast, telomere maintenance is a key feature of human malignant cells and required for their infinite proliferation and maintenance of other cancer hallmarks as well. Thus, a telomere-based anti-cancer strategy has long been suggested. However, clinically efficient and specific drugs targeting cancer telomere-maintenance have still been in their infancy thus far. To achieve this goal, it is highly necessary to elucidate how exactly cancer cells maintain functional telomeres. In the last two decades, numerous studies have provided profound mechanistic insights, and the identified mechanisms include the aberrant activation of telomerase or the alternative lengthening of telomere pathway responsible for telomere elongation, dysregulation and mutation of telomereassociated factors, and other telomere homeostasis-related signaling nodes. In the present review, these various strategies employed by malignant cells to regulate their telomere length, structure and function have been summarized, and potential implications of these findings in the rational development of telomere- based cancer therapy and other clinical applications for precision oncology have been discussed.

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Bateson, Melissa, and Daniel Nettle. "Why are there associations between telomere length and behaviour?" Philosophical Transactions of the Royal Society B: Biological Sciences 373, no. 1741 (January 15, 2018): 20160438. http://dx.doi.org/10.1098/rstb.2016.0438.

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Individual differences in telomere length are associated with individual differences in behaviour in humans and birds. Within the human epidemiological literature this association is assumed to result from specific behaviour patterns causing changes in telomere dynamics. We argue that selective adoption—the hypothesis that individuals with short telomeres are more likely to adopt specific behaviours—is an alternative worthy of consideration. Selective adoption could occur either because telomere length directly affects behaviour or because behaviour and telomere length are both affected by a third variable, such as exposure to early-life adversity. We present differential predictions of the causation and selective adoption hypotheses and describe how these could be tested with longitudinal data on telomere length. Crucially, if behaviour is causal then it should be associated with differential rates of telomere attrition. Using smoking behaviour as an example, we show that the evidence that smoking accelerates the rate of telomere attrition within individuals is currently weak. We conclude that the selective adoption hypothesis for the association between behaviour and telomere length is both mechanistically plausible and, if anything, more compatible with existing empirical evidence than the hypothesis that behaviour is causal. This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.

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Bechard, Laura H., Bilge D. Butuner, George J. Peterson, Will McRae, Zeki Topcu, and Michael J. McEachern. "Mutant Telomeric Repeats in Yeast Can Disrupt the Negative Regulation of Recombination-Mediated Telomere Maintenance and Create an Alternative Lengthening of Telomeres-Like Phenotype." Molecular and Cellular Biology 29, no. 3 (November 24, 2008): 626–39. http://dx.doi.org/10.1128/mcb.00423-08.

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ABSTRACT Some human cancers maintain telomeres using alternative lengthening of telomeres (ALT), a process thought to be due to recombination. In Kluyveromyces lactis mutants lacking telomerase, recombinational telomere elongation (RTE) is induced at short telomeres but is suppressed once telomeres are moderately elongated by RTE. Recent work has shown that certain telomere capping defects can trigger a different type of RTE that results in much more extensive telomere elongation that is reminiscent of human ALT cells. In this study, we generated telomeres composed of either of two types of mutant telomeric repeats, Acc and SnaB, that each alter the binding site for the telomeric protein Rap1. We show here that arrays of both types of mutant repeats present basally on a telomere were defective in negatively regulating telomere length in the presence of telomerase. Similarly, when each type of mutant repeat was spread to all chromosome ends in cells lacking telomerase, they led to the formation of telomeres produced by RTE that were much longer than those seen in cells with only wild-type telomeric repeats. The Acc repeats produced the more severe defect in both types of telomere maintenance, consistent with their more severe Rap1 binding defect. Curiously, although telomerase deletion mutants with telomeres composed of Acc repeats invariably showed extreme telomere elongation, they often also initially showed persistent very short telomeres with few or no Acc repeats. We suggest that these result from futile cycles of recombinational elongation and truncation of the Acc repeats from the telomeres. The presence of extensive 3′ overhangs at mutant telomeres suggests that Rap1 may normally be involved in controlling 5′ end degradation.

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Kalmbach, Keri, LeRoy G. Robinson, Fang Wang, Lin Liu, and David Keefe. "Telomere Length Reprogramming in Embryos and Stem Cells." BioMed Research International 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/925121.

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Telomeres protect and cap linear chromosome ends, yet these genomic buffers erode over an organism’s lifespan. Short telomeres have been associated with many age-related conditions in humans, and genetic mutations resulting in short telomeres in humans manifest as syndromes of precocious aging. In women, telomere length limits a fertilized egg’s capacity to develop into a healthy embryo. Thus, telomere length must be reset with each subsequent generation. Although telomerase is purportedly responsible for restoring telomere DNA, recent studies have elucidated the role of alternative telomeres lengthening mechanisms in the reprogramming of early embryos and stem cells, which we review here.

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Lin, Chi-Ying, Hsih-Hsuan Chang, Kou-Juey Wu, Shun-Fu Tseng, Chuan-Chuan Lin, Chao-Po Lin, and Shu-Chun Teng. "Extrachromosomal Telomeric Circles Contribute to Rad52-, Rad50-, and Polymerase δ-Mediated Telomere-Telomere Recombination in Saccharomyces cerevisiae." Eukaryotic Cell 4, no. 2 (February 2005): 327–36. http://dx.doi.org/10.1128/ec.4.2.327-336.2005.

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ABSTRACT Telomere maintenance is required for chromosome stability, and telomeres are typically replicated by the telomerase reverse transcriptase. In both tumor and yeast cells that lack telomerase, telomeres are maintained by an alternative recombination mechanism. By using an in vivo inducible Cre-loxP system to generate and trace the fate of marked telomeric DNA-containing rings, the efficiency of telomere-telomere recombination can be determined quantitatively. We show that the telomeric loci are the primary sites at which a marked telomeric ring-containing DNA is observed among wild-type and surviving cells lacking telomerase. Marked telomeric DNAs can be transferred to telomeres and form tandem arrays through Rad52-, Rad50-, and polymerase δ-mediated recombination. Moreover, increases of extrachromosomal telomeric and Y′ rings were observed in telomerase-deficient cells. These results imply that telomeres can use looped-out telomeric rings to promote telomere-telomere recombination in telomerase-deficient Saccharomyces cerevisiae.

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De Vitis, Marco, Francesco Berardinelli, Elisa Coluzzi, Jessica Marinaccio, Roderick J. O’Sullivan, and Antonella Sgura. "X-rays Activate Telomeric Homologous Recombination Mediated Repair in Primary Cells." Cells 8, no. 7 (July 12, 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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Journal articles on the topic 'Alternative Verlängerung der Telomere'

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