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 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 Erratum: Homologous recombination in Candida albicans: role of CaRad52p in DNA repair, integration of linear DNA fragments and telomere length

2005 ◽  
Vol 56 (5) ◽  
pp. 1396-1396 ◽  
Author(s):  
Toni Ciudad ◽  
Encarnación Andaluz ◽  
Olga Steinberg-Neifach ◽  
Neal F. Lue ◽  
Neil A. R. Gow ◽  
...  
Keyword(s):  
Dna Repair ◽  
Candida Albicans ◽  
Homologous Recombination ◽  
Telomere Length ◽  
Dna Fragments ◽  
Linear Dna

scholarly journals The Role of Rif1 in telomere length regulation is separable from its role in origin firing

2020 ◽  
Author(s):  
Calla B. Shubin ◽  
Carol W. Greider
Keyword(s):  
Telomere Length ◽  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Origin Firing ◽  
Replication Complex ◽  
Telomere Elongation ◽  
Length Regulation ◽  
Telomere Length Regulation ◽  
Telomere Lengthening

AbstractTo examine the established link between DNA replication and telomere length, we tested whether firing of telomeric origins would cause telomere lengthening. We found that RIF1 mutants that block Protein Phosphatase 1 (PP1) binding activated telomeric origins but did not elongate telomeres. In a second approach, we found overexpression of ΔN-Dbf4 and Cdc7 increased DDK activity and activated telomeric origins, yet telomere length was unchanged. We tested a third mechanism to activate origins using the sld3-A mcm5-bob1 mutant that deregulates the pre-replication complex, and again saw no change in telomere length. Finally, we tested whether mutations in RIF1 that cause telomere elongation would affect origin firing. We found that neither rif1-Δ1322 nor rif1HOOK affected firing of telomeric origins. We conclude that telomeric origin firing does not cause telomere elongation, and the role of Rif1 in regulating origin firing is separable from its role in regulating telomere length.

scholarly journals Telomeres and Cancer

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1405
Author(s):  
Hueng-Chuen Fan ◽  
Fung-Wei Chang ◽  
Jeng-Dau Tsai ◽  
Kao-Min Lin ◽  
Chuan-Mu Chen ◽  
...  
Keyword(s):  
Telomere Length ◽  
Molecular Mechanisms ◽  
Telomere Maintenance ◽  
Cancer Development ◽  
Telomere Elongation ◽  
Metabolism Pathway ◽  
Length Regulation ◽  
Telomere Length Regulation ◽  
Genome Protection

Telomeres cap the ends of eukaryotic chromosomes and are indispensable chromatin structures for genome protection and replication. Telomere length maintenance has been attributed to several functional modulators, including telomerase, the shelterin complex, and the CST complex, synergizing with DNA replication, repair, and the RNA metabolism pathway components. As dysfunctional telomere maintenance and telomerase activation are associated with several human diseases, including cancer, the molecular mechanisms behind telomere length regulation and protection need particular emphasis. Cancer cells exhibit telomerase activation, enabling replicative immortality. Telomerase reverse transcriptase (TERT) activation is involved in cancer development through diverse activities other than mediating telomere elongation. This review describes the telomere functions, the role of functional modulators, the implications in cancer development, and the future therapeutic opportunities.

scholarly journals The role of Rif1 in telomere length regulation is separable from its role in origin firing

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Calla B Shubin ◽  
Carol W Greider
Keyword(s):  
Telomere Length ◽  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Origin Firing ◽  
Replication Complex ◽  
Telomere Elongation ◽  
Length Regulation ◽  
Telomere Length Regulation ◽  
Telomere Lengthening

To examine the established link between DNA replication and telomere length, we tested whether firing of telomeric origins would cause telomere lengthening. We found that RIF1 mutants that block Protein Phosphatase 1 (PP1) binding activated telomeric origins but did not elongate telomeres. In a second approach, we found overexpression of ∆N-Dbf4 and Cdc7 increased DDK activity and activated telomeric origins, yet telomere length was unchanged. We tested a third mechanism to activate origins using the sld3-A mcm5-bob1 mutant that de-regulates the pre-replication complex, and again saw no change in telomere length. Finally, we tested whether mutations in RIF1 that cause telomere elongation would affect origin firing. We found that neither rif1-∆1322 nor rif1HOOK affected firing of telomeric origins. We conclude that telomeric origin firing does not cause telomere elongation, and the role of Rif1 in regulating origin firing is separable from its role in regulating telomere length.

scholarly journals Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Timothy P. Lippert ◽  
Paulina Marzec ◽  
Aurora I. Idilli ◽  
Grzegorz Sarek ◽  
Aleksandra Vancevska ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Telomere Maintenance ◽  
Alternative Lengthening Of Telomeres ◽  
Telomere Shortening ◽  
Alternative Lengthening ◽  
A Cell ◽  
Infected Cells ◽  
Break Induced Replication ◽  
Alt Activity

AbstractTo achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms to prevent telomere shortening. ~85% of cancers circumvent telomeric attrition by re-expressing telomerase, while the remaining ~15% of cancers induce alternative lengthening of telomeres (ALT), which relies on break-induced replication (BIR) and telomere recombination. Although ALT tumours were first reported over 20 years ago, the mechanism of ALT induction remains unclear and no study to date has described a cell-based model that permits the induction of ALT. Here, we demonstrate that infection with Kaposi’s sarcoma herpesvirus (KSHV) induces sustained acquisition of ALT-like features in previously non-ALT cell lines. KSHV-infected cells acquire hallmarks of ALT activity that are also observed in KSHV-associated tumour biopsies. Down-regulating BIR impairs KSHV latency, suggesting that KSHV co-opts ALT for viral functionality. This study uncovers KSHV infection as a means to study telomere maintenance by ALT and reveals features of ALT in KSHV-associated tumours.

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 TCGA Pan-Cancer genomic analysis of Alternative Lengthening of Telomeres (ALT) related genes

2020 ◽  
Author(s):  
Isaac Armendáriz-Castillo ◽  
Andrés López-Cortés ◽  
Jennyfer García-Cárdenas ◽  
Patricia Guevara-Ramírez ◽  
Paola E. Leone ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Genomic Analysis ◽  
Interaction Network ◽  
Telomere Maintenance ◽  
The Cancer Genome Atlas ◽  
Alternative Lengthening Of Telomeres ◽  
Alternative Lengthening ◽  
Pan Cancer

AbstractTelomere maintenance mechanisms (TMM) are used by cancer cells to avoid apoptosis, 85-90% reactivate telomerase, while 10-15% use the alternative lengthening of telomeres (ALT). Due to anti-telomerase-based treatments, some tumors have the ability to switch from a telomerase-dependent mechanism to ALT, in fact, the co-existence between telomerase and the ALT pathway have been observed in a variety of cancer types. Despite different elements in the ALT pathway have been uncovered, the molecular mechanism and other factors are still poorly understood, which difficult the detection and treatment of ALT-positive cells, which are known to present poor prognosis. Therefore, with the aim to identify potential molecular markers to be used in the study of ALT, we combined simplistic in silico approaches in 411 telomere maintenance (TM) genes which have been previously validated or predicted to be involved in the ALT pathway. In consequence, we conducted a genomic analysis of these genes in 31 Pan-Cancer Atlas studies (n=9,282) from The Cancer Genome Atlas in the cBioPortal and found 325,936 genomic alterations, being mRNA high and low the top alterations with 65,.8% and 10.7% respectively. Moreover, we analyzed the highest frequency means of genomics alterations, identified and proposed 20 genes, which are highly mutated and up and down regulated in the cancer studies and could be used for future analysis in the study of ALT. Finally, we made a protein-protein interaction network and enrichment analysis to obtain an insight into the main pathways these genes are involved. We could observe their role in main processes related to the ALT mechanism like homologous recombination, homology directed repair (HDR), HDR through homologous recombination and telomere maintenance and organization.. Overall, due to the lack of understanding of the molecular mechanisms and detection of ALT-positive cancers, we identified and proposed more molecular targets that can be used for expression analysis and additional ex vivo assays to validate them as new potential therapeutic markers in the study of the ALT mechanism.

scholarly journals Expression of Telomerase RNA Template, but Not Telomerase Reverse Transcriptase, Is Limiting for Telomere Length Maintenance In Vivo

2004 ◽  
Vol 24 (16) ◽  
pp. 7024-7031 ◽  
Author(s):  
Y. Jeffrey Chiang ◽  
Michael T. Hemann ◽  
Karen S. Hathcock ◽  
Lino Tessarollo ◽  
Lionel Feigenbaum ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Telomere Length ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Gene Copy ◽  
Telomerase Reverse Transcriptase ◽  
Telomerase Rna ◽  
Wild Type ◽  
Telomere Elongation

ABSTRACT Telomerase consists of two essential components, the telomerase RNA template (TR) and telomerase reverse transcriptase (TERT). The haplo-insufficiency of TR was recently shown to cause one form of human dyskeratosis congenita, an inherited disease marked by abnormal telomere shortening. Consistent with this finding, we recently reported that mice heterozygous for inactivation of mouse TR exhibit a similar haplo-insufficiency and are deficient in the ability to elongate telomeres in vivo. To further assess the genetic regulation of telomerase activity, we have compared the abilities of TR-deficient and TERT-deficient mice to maintain or elongate telomeres in interspecies crosses. Homozygous TERT knockout mice had no telomerase activity and failed to maintain telomere length. In contrast, TERT+/− heterozygotes had no detectable defect in telomere elongation compared to wild-type controls, whereas TR+/− heterozygotes were deficient in telomere elongation. Levels of TERT mRNA in heterozygous mice were one-third to one-half the levels expressed in wild-type mice, similar to the reductions in telomerase RNA observed in TR heterozygotes. These findings indicate that both TR and TERT are essential for telomere maintenance and elongation but that gene copy number and transcriptional regulation of TR, but not TERT, are limiting for telomerase activity under the in vivo conditions analyzed.

Sign in / Sign up

Export Citation Format

Share Document