scholarly journals Telomerase-Independent Telomere Length Maintenance in the Absence of Alternative Lengthening of Telomeres–Associated Promyelocytic Leukemia Bodies

2005 ◽  
Vol 65 (7) ◽  
pp. 2722-2729 ◽  
Author(s):  
Clare L. Fasching ◽  
Kylie Bower ◽  
Roger R. Reddel
Keyword(s):  
Telomere Length ◽  
Promyelocytic Leukemia ◽  
Alternative Lengthening Of Telomeres ◽  
Alternative Lengthening

scholarly journals Suppression of Alternative Lengthening of Telomeres by Sp100-Mediated Sequestration of the MRE11/RAD50/NBS1 Complex

2005 ◽  
Vol 25 (7) ◽  
pp. 2708-2721 ◽  
Author(s):  
Wei-Qin Jiang ◽  
Ze-Huai Zhong ◽  
Jeremy D. Henson ◽  
Axel A. Neumann ◽  
Andy C.-M. Chang ◽  
...  
Keyword(s):  
Dna Replication ◽  
Telomere Length ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
Population Doubling ◽  
Telomeric Dna ◽  
Alternative Lengthening Of Telomeres ◽  
Telomere Shortening ◽  
Alternative Lengthening ◽  
Length Changes

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.

scholarly journals Alternative Lengthening of Telomeres and Chromatin Status

Genes ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 45 ◽  
Author(s):  
Ion Udroiu ◽  
Antonella Sgura
Keyword(s):  
Homologous Recombination ◽  
Reverse Transcriptase ◽  
Spatial Heterogeneity ◽  
Telomere Length ◽  
Epigenetic Modifications ◽  
Alternative Lengthening Of Telomeres ◽  
Telomere Elongation ◽  
Alternative Lengthening ◽  
Alt Activity

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.

scholarly journals Telomerase and Alternative Lengthening of Telomeres coexist in the regenerating zebrafish caudal fins

2021 ◽  
Author(s):  
Maria L. Cayuela ◽  
Elena Martínez-Balsalobre ◽  
Monique Anchelin-Flageul ◽  
Francisca Alcaraz-Perez ◽  
Jesús García-Castillo ◽  
...  
Keyword(s):  
Telomere Length ◽  
Molecular Mechanisms ◽  
Regeneration Process ◽  
Wild Type ◽  
Alternative Lengthening Of Telomeres ◽  
Zebrafish Model ◽  
Alternative Lengthening ◽  
Vertebrate Model ◽  
New Treatments ◽  
Dependent Processes

Telomeres are essential for chromosome protection and genomic stability, and telomerase function is critical to organ homeostasis. Zebrafish has become a useful vertebrate model for understanding the cellular and molecular mechanisms of regeneration. The regeneration capacity of the caudal fin of wild-type zebrafish is not affected by repetitive amputation, but the behavior of telomeres during this process has not yet been studied. In this study, the regeneration process was characterized in a telomerase deficient zebrafish model. Moreover, the regenerative capacity after repetitive amputations and at different ages was studied. Regenerative efficiency decreases with aging in all genotypes and surprisingly, telomere length is maintained even in telomerase deficient genotypes. Our results suggest that telomere length can be maintained by the regenerating cells through the recombination-mediated Alternative Lengthening of Telomeres (ALT) pathway, which is likely to support high rates of cell proliferation during the tailfin regeneration process. As far as we know, this is the first animal model to study ALT mechanism in regeneration, which opens a wealth of possibilities to study new treatments of ALT dependent processes.

scholarly journals Alternative lengthening of telomeres in molecular subgroups of paediatric high-grade glioma

2020 ◽  
Author(s):  
Simone Minasi ◽  
Caterina Baldi ◽  
Francesca Gianno ◽  
Manila Antonelli ◽  
Anna Maria Buccoliero ◽  
...  
Keyword(s):  
Telomere Length ◽  
Strong Association ◽  
High Grade Glioma ◽  
Genetic Alterations ◽  
High Grade ◽  
Molecular Subgroups ◽  
Alternative Lengthening Of Telomeres ◽  
Telomere Elongation ◽  
K27m Mutation ◽  
Alternative Lengthening

Abstract Purpose The maintenance of telomere length prevents cancer cell senescence and occurs via two mutually exclusive mechanisms: (a) reactivation of telomerase expression and (b) activation of alternative lengthening of telomeres (ALT). ALT is frequently related to alterations on ATRX, a chromatin-remodelling protein. Recent data have identified different molecular subgroups of paediatric high-grade glioma (pHGG) with mutations of H3F3A, TERTp and ATRX; however, differences in telomere length among these molecular subgroups were not thoroughly examined. Methods We investigated which genetic alterations trigger the ALT mechanism in 52 IDH-wildtype, 1p/19q-wildtype pHGG. Samples were analysed for telomere length using Tel-FISH. ATRX nuclear loss of expression was assessed by IHC, H3F3A and TERTp mutations by DNA sequencing, and TERTp methylation by MS-PCR. Results Mutant H3.3 was found in 21 cases (40.3%): 19.2% with K27M mutation and 21.1% with G34R mutation. All H3.3G34R-mutated cases showed the ALT phenotype (100%); on the opposite, only 40% of the H3.3K27M-mutated showed ALT activation. ATRX nuclear loss was seen in 16 cases (30.7%), associated sometimes with the G34R mutation, and never with the K27M mutation. ATRX nuclear loss was always related to telomere elongation. TERTp C250T mutations were rare (5.4%) and were not associated with high intensity Tel-FISH signals, as TERTp hyper-methylation detected in 21% of the cases. H3.3/ATRX/TERTp-wildtype pHGG revealed all basal levels of telomere length. Conclusion Our results show a strong association between H3.3 mutations and ALT, and highlight the different telomeric profiles in histone-defined subgroups: H3.3-G34R mutants always trigger ALT to maintain telomere length, irrespective of ATRX status, whereas only some H3.3-K27M tumours activate ALT. These findings suggest that acquiring the gly34 mutation on H3.3 might suffice to trigger the ALT mechanism.

scholarly journals Coexistence of Alternative Lengthening of Telomeres and Telomerase in hTERT-Transfected GM847 Cells

2001 ◽  
Vol 21 (12) ◽  
pp. 3862-3875 ◽  
Author(s):  
Kilian Perrem ◽  
Lorel M. Colgin ◽  
Axel A. Neumann ◽  
Thomas R. Yeager ◽  
Roger R. Reddel
Keyword(s):  
Cell Line ◽  
Telomerase Activity ◽  
Promyelocytic Leukemia ◽  
Tumor Cell Lines ◽  
Hybrid Cells ◽  
Alternative Lengthening Of Telomeres ◽  
Positive Tumor Cell ◽  
Alternative Lengthening ◽  
Pml Bodies ◽  
Population Doublings

ABSTRACT It has been shown previously that some immortalized human cells maintain their telomeres in the absence of significant levels of telomerase activity by a mechanism referred to as alternative lengthening of telomeres (ALT). Cells utilizing ALT have telomeres of very heterogeneous length, ranging from very short to very long. Here we report the effect of telomerase expression in the ALT cell line GM847. Expression of exogenous hTERT in GM847 (GM847/hTERT) cells resulted in lengthening of the shortest telomeres; this is the first evidence that expression of hTERT in ALT cells can induce telomerase that is active at the telomere. However, rapid fluctuation in telomere length still occurred in the GM847/hTERT cells after more than 100 population doublings. Very long telomeres and ALT-associated promyelocytic leukemia (PML) bodies continued to be generated, indicating that telomerase activity induced by exogenous hTERT did not abolish the ALT mechanism. In contrast, when the GM847 cell line was fused with two different telomerase-positive tumor cell lines, the ALT phenotype was repressed in each case. These hybrid cells were telomerase positive, and the telomeres decreased in length, very rapidly at first and then at the rate seen in telomerase-negative normal cells. Additionally, ALT-associated PML bodies disappeared. After the telomeres had shortened sufficiently, they were maintained at a stable length by telomerase. Together these data indicate that the telomerase-positive cells contain a factor that represses the ALT mechanism but that this factor is unlikely to be telomerase. Further, the transfection data indicate that ALT and telomerase can coexist in the same cells.

scholarly journals Identification of Key Proteins in the Alternative Lengthening of Telomeres Associated Promyelocytic Leukemia Nuclear Bodies

2021 ◽  
Author(s):  
Isaac Armendáriz-Castillo ◽  
Katherine Hidalgo-Fernández ◽  
Andy Pérez-Villa ◽  
Jennyfer García-Cárdenas ◽  
Andrés López-Cortés ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Promyelocytic Leukemia ◽  
Nuclear Bodies ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Alternative Lengthening Of Telomeres ◽  
Pml Nuclear Bodies ◽  
Alternative Lengthening

One of the hallmarks of the Alternative Lengthening of Telomeres (ALT) is the association with Promyelocytic Leukemia (PML) Nuclear Bodies, known as APBs. In the last years, APBs have been described as the main place where telomeric extension occurs in ALT positive cancer cell lines. A different set of proteins have been associated with APBs function, however, the molecular mechanisms behind their assembly, colocalization, and clustering of telomeres, among others, remain unclear. To improve the understanding of APBs in the ALT pathway, we integrated multi-omics analyses to evaluate genomic, transcriptomic and proteomic alterations, and functional interactions of 71 APBs-related genes/proteins in 32 PanCancer Atlas studies from The Cancer Genome Atlas Consortium (TCGA). As a result, we identified 13 key proteins which showed distinctive mutations, interactions, and functional enrichment patterns across all the cancer types and proposed this set of proteins as candidates for future ex vivo and in vivo analyses that will validate these proteins to improve the understanding of the ALT pathway, fill the current research gap about APBs function and their role in ALT, and be considered as potential therapeutic targets for the diagnosis and treatment of ALT positive cancers in the future.

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