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 Cancer cells with alternative lengthening of telomeres do not display a general hypersensitivity to ATR inhibition

2016 ◽  
Author(s):  
Katharina I. Deeg ◽  
Inn Chung ◽  
Caroline Bauer ◽  
Karsten Rippe
Keyword(s):  
Cell Viability ◽  
Cancer Cells ◽  
Cell Lines ◽  
Ataxia Telangiectasia ◽  
Telomere Maintenance ◽  
Alternative Lengthening Of Telomeres ◽  
Isogenic Cell Line ◽  
Alternative Lengthening ◽  
Cellular Immortality ◽  
Proliferation Potential

AbstractTelomere maintenance is a hallmark of cancer as it provides cancer cells with cellular immortality. A significant fraction of tumors uses the alternative lengthening of telomeres (ALT) pathway to elongate their telomeres and to gain an unlimited proliferation potential. Since the ALT pathway is unique to cancer cells, it represents a potentially valuable, currently unexploited target for anticancer therapies. Recently, it was proposed that ALT renders cells hypersensitive to ataxia telangiectasia-and RAD3-related (ATR) protein inhibitors (Flynn et al., Science 347, 273). Here, we measured the response of various ALT or telomerase positive cell lines to the ATR inhibitor VE-821. In addition, we compared the effect of the inhibitor on cell viability in an isogenic cell line, in which ALT was active or suppressed. In these experiments a general ATR inhibitor sensitivity of cells with ALT could not be confirmed. We rather propose that the observed variations in sensitivity reflect differences between cell lines that are unrelated to ALT.

scholarly journals ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner

PLoS ONE ◽  
2018 ◽  
Vol 13 (9) ◽  
pp. e0204159 ◽  
Author(s):  
Jacqueline A. Brosnan-Cashman ◽  
Ming Yuan ◽  
Mindy K. Graham ◽  
Anthony J. Rizzo ◽  
Kaylar M. Myers ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Glioma Cell ◽  
Human Glioma ◽  
Alternative Lengthening Of Telomeres ◽  
Human Glioma Cell ◽  
Alternative Lengthening ◽  
Glioma Cell Lines ◽  
Specific Manner ◽  
A Cell

scholarly journals The level of activity of the alternative lengthening of telomeres correlates with patient age in IDH-mutant ATRX-loss-of-expression anaplastic astrocytomas

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Nathalie Grandin ◽  
◽  
Bruno Pereira ◽  
Camille Cohen ◽  
Pauline Billard ◽  
...  
Keyword(s):  
Activity Level ◽  
Telomere Maintenance ◽  
Alternative Lengthening Of Telomeres ◽  
Patient Age ◽  
Alternative Lengthening ◽  
Level Of Activity ◽  
Patient Âgé ◽  
Diffuse Gliomas ◽  
Cancer Types ◽  
Alt Activity

Abstract All cancer cells need to maintain functional telomeres to sustain continuous cell division and proliferation. In human diffuse gliomas, functional telomeres are maintained due either to reactivation of telomerase expression, the main pathway in most cancer types, or to activation of a mechanism called the alternative lengthening of telomeres (ALT). The presence of IDH1/2 mutations (IDH-mutant) together with loss of ATRX expression (ATRX-lost) are frequently associated with ALT in diffuse gliomas. However, detection of ALT, and a fortiori its quantification, are rarely, if ever, measured in neuropathology laboratories. We measured the level of ALT activity using the previously described quantitative “C-circle” assay and analyzed it in a well characterized cohort of 104 IDH-mutant and ATRX-lost adult diffuse gliomas. We report that in IDH-mutant ATRX-lost anaplastic astrocytomas, the intensity of ALT was inversely correlated with age (p < 0.001), the younger the patient, the higher the intensity of ALT. Strikingly, glioblastomas having progressed from anaplastic astrocytomas did not exhibit this correlation. ALT activity level in the tumor did not depend on telomere length in healthy tissue cells from the same patient. In summary, we have uncovered the existence, in anaplastic astrocytomas but not in glioblastomas with the same IDH and ATRX mutations, of a correlation between patient age and the level of activity of ALT, a telomerase-independent pathway of telomere maintenance.

scholarly journals Alternative Lengthening of Telomeres Mediated by Mitotic DNA Synthesis Engages Break-Induced Replication Processes

2017 ◽  
Vol 37 (20) ◽  
Author(s):  
Jaewon Min ◽  
Woodring E. Wright ◽  
Jerry W. Shay
Keyword(s):  
Dna Synthesis ◽  
Telomere Maintenance ◽  
Synthesis Process ◽  
Loop Formation ◽  
Alternative Lengthening Of Telomeres ◽  
Independent Manner ◽  
Content Type ◽  
Alternative Lengthening ◽  
Telomere Replication ◽  
Break Induced Replication

ABSTRACT Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. By analyzing telomerase-positive cells and their human TERC knockout-derived ALT human cell lines, we show that ALT cells harbor more fragile telomeres representing telomere replication problems. ALT-associated replication defects trigger mitotic DNA synthesis (MiDAS) at telomeres in a RAD52-dependent, but RAD51-independent, manner. Telomeric MiDAS is a conservative DNA synthesis process, potentially mediated by break-induced replication, similar to type II ALT survivors in Saccharomyces cerevisiae. Replication stresses induced by ectopic oncogenic expression of cyclin E, G-quadruplexes, or R-loop formation facilitate the ALT pathway and lead to telomere clustering, a hallmark of ALT cancers. The TIMELESS/TIPIN complex suppresses telomere clustering and telomeric MiDAS, whereas the SMC5/6 complex promotes them. In summary, ALT cells exhibit more telomere replication defects that result in persistent DNA damage responses at telomeres, leading to the engagement of telomeric MiDAS (spontaneous mitotic telomere synthesis) that is triggered by DNA replication stress, a potential driver of genomic duplications in cancer.

scholarly journals Induction of the ALT pathway requires loss of ATRX-DAXX in concert with genotoxic lesions at telomeres

2021 ◽  
Author(s):  
David Clynes ◽  
Tomas Goncalves ◽  
Thomas Kent ◽  
Sam Shepherd ◽  
Siobhan Cunniffe ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Sister Chromatid ◽  
Sister Chromatid Cohesion ◽  
Tumour Suppressor ◽  
High Grade ◽  
Alternative Lengthening Of Telomeres ◽  
Alternative Lengthening ◽  
Chromatid Cohesion ◽  
Telomere Lengthening ◽  
Break Induced Replication

Abstract A key requisite for indefinite growth of cancer cells is the ability to continuously elongate telomeres to circumvent the onset of senescence or apoptosis. In approximately 10 – 15% of cancers this is achieved through the Alternative Lengthening of Telomeres (ALT) pathway, a Break Induced Replication (BIR) mediated mechanism of telomere copying. ATRX has emerged as the key tumour suppressor in ALT cancers but its loss is insufficient to drive induction of the pathway. Here, we report that depletion of ATRX and/or DAXX in the presence of various genotoxic agents is sufficient to induce ALT. Moreover, co-deletion of ATRX and SETD2, commonly mutated in high grade gliomas (HGGs), elicits induction of ALT. Mechanistically, SETD2 restricts the accumulation of telomeric R-loops, which, in the absence of ATRX, leads to fork collapse and the loss of telomere sister chromatid cohesion. Cumulatively this provides a substrate for out of register BIR and telomere lengthening.

scholarly journals ALT Positivity in Human Cancers: Prevalence and Clinical Insights

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2384
Author(s):  
Danny MacKenzie Jr. ◽  
Andrea K. Watters ◽  
Julie T. To ◽  
Melody W. Young ◽  
Jonathan Muratori ◽  
...  
Keyword(s):  
Clinical Investigation ◽  
Management Strategies ◽  
Telomere Maintenance ◽  
Alternative Lengthening Of Telomeres ◽  
Mutation Status ◽  
Cancer Subtypes ◽  
Alternative Lengthening ◽  
Telomere Biology ◽  
The Relationship ◽  
Alt Activity

Since it was first described over two decades ago, the Alternative Lengthening of Telomeres (ALT) pathway has been well accepted to hold clinical significance in cancer development, cancer diagnosis and cancer treatment. In this review, we first discuss how the activation of this pathway is determined. We then provide up-to-date statistics on the cancers ALT activity is detected. Additionally, we discussed the relationship between ALT positivity and prognosis as well as the pathogenetics of the ALT positive cancers. Finally, we evaluated the pre-clinical and clinical investigation of potential therapy for ALT cancers.Abstract: Many exciting advances in cancer-related telomere biology have been made in the past decade. Of these recent advances, great progress has also been made with respect to the Alternative Lengthening of Telomeres (ALT) pathway. Along with a better understanding of the molecular mechanism of this unique telomere maintenance pathway, many studies have also evaluated ALT activity in various cancer subtypes. We first briefly review and assess a variety of commonly used ALT biomarkers. Then, we provide both an update on ALT-positive (ALT+) tumor prevalence as well as a systematic clinical assessment of the presently studied ALT+ malignancies. Additionally, we discuss the pathogenetic alterations in ALT+ cancers, for example, the mutation status of ATRX and DAXX, and their correlations with the activation of the ALT pathway. Finally, we highlight important ALT+ clinical associations within each cancer subtype and subdivisions within, as well as their prognoses. We hope this alternative perspective will allow scientists, clinicians, and drug developers to have greater insight into the ALT cancers so that together, we may develop more efficacious treatments and improved management strategies to meet the urgent needs of cancer patients.

scholarly journals Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sabine A. Hartlieb ◽  
Lina Sieverling ◽  
Michal Nadler-Holly ◽  
Matthias Ziehm ◽  
Umut H. Toprak ◽  
...  
Keyword(s):  
High Frequency ◽  
Clinical Course ◽  
Population Based ◽  
Telomeric Repeat ◽  
Telomere Maintenance ◽  
Study Cohort ◽  
Alternative Lengthening Of Telomeres ◽  
Course Of Disease ◽  
Low Protein ◽  
Alternative Lengthening

AbstractTelomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome.

scholarly journals Nuclear receptors regulate alternative lengthening of telomeres through a novel noncanonical FANCD2 pathway

2019 ◽  
Vol 5 (10) ◽  
pp. eaax6366 ◽  
Author(s):  
Mafei Xu ◽  
Jun Qin ◽  
Leiming Wang ◽  
Hui-Ju Lee ◽  
Chung-Yang Kao ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Direct Interaction ◽  
Telomere Maintenance ◽  
Telomeric Dna ◽  
Core Complex ◽  
Alternative Lengthening Of Telomeres ◽  
Independent Manner ◽  
Replication Complex ◽  
Alternative Lengthening ◽  
Key Steps

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.

scholarly journals The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 949 ◽  
Author(s):  
Marta Recagni ◽  
Joanna Bidzinska ◽  
Nadia Zaffaroni ◽  
Marco Folini
Keyword(s):  
Cancer Cells ◽  
Tumor Biology ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Limited Information ◽  
Adaptive Responses ◽  
Therapeutic Implications ◽  
Telomerase Inhibitors ◽  
Alternative Lengthening

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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