Abstract LB-084: A role of long interspersed nuclear element-1 (LINE-1) for telomere maintenance in cells with alternative lengthening of telomeres

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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Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome

Nature Communications ◽

10.1038/s41467-021-21247-8 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 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.

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Endogenous oxidized DNA bases and APE1 regulate the formation of G-quadruplex structures in the genome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1912355117 ◽

2020 ◽

Vol 117 (21) ◽

pp. 11409-11420 ◽

Cited By ~ 4

Author(s):

Shrabasti Roychoudhury ◽

Suravi Pramanik ◽

Hannah L. Harris ◽

Mason Tarpley ◽

Aniruddha Sarkar ◽

...

Keyword(s):

Excision Repair ◽

Factor Loading ◽

Telomere Maintenance ◽

Epigenetic Mechanism ◽

Dna Bases ◽

G Quadruplex ◽

Base Excision ◽

Ap Site ◽

In Cells

Formation of G-quadruplex (G4) DNA structures in key regulatory regions in the genome has emerged as a secondary structure-based epigenetic mechanism for regulating multiple biological processes including transcription, replication, and telomere maintenance. G4 formation (folding), stabilization, and unfolding must be regulated to coordinate G4-mediated biological functions; however, how cells regulate the spatiotemporal formation of G4 structures in the genome is largely unknown. Here, we demonstrate that endogenous oxidized guanine bases in G4 sequences and the subsequent activation of the base excision repair (BER) pathway drive the spatiotemporal formation of G4 structures in the genome. Genome-wide mapping of occurrence of Apurinic/apyrimidinic (AP) site damage, binding of BER proteins, and G4 structures revealed that oxidized base-derived AP site damage and binding of OGG1 and APE1 are predominant in G4 sequences. Loss of APE1 abrogated G4 structure formation in cells, which suggests an essential role of APE1 in regulating the formation of G4 structures in the genome. Binding of APE1 to G4 sequences promotes G4 folding, and acetylation of APE1, which enhances its residence time, stabilizes G4 structures in cells. APE1 subsequently facilitates transcription factor loading to the promoter, providing mechanistic insight into the role of APE1 in G4-mediated gene expression. Our study unravels a role of endogenous oxidized DNA bases and APE1 in controlling the formation of higher-order DNA secondary structures to regulate transcription beyond its well-established role in safeguarding the genomic integrity.

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

Science Advances ◽

10.1126/sciadv.aax6366 ◽

2019 ◽

Vol 5 (10) ◽

pp. eaax6366 ◽

Cited By ~ 8

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.

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

Cancers ◽

10.3390/cancers12040949 ◽

2020 ◽

Vol 12 (4) ◽

pp. 949 ◽

Cited By ~ 4

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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Abstract 4767: Generating and characterizing novel prostate cancer cell lines that employ the alternative lengthening of telomeres (ALT) telomere maintenance mechanism

10.1158/1538-7445.am2016-4767 ◽

2016 ◽

Author(s):

Mindy K. Graham ◽

Jacqueline Brosnan-Cashman ◽

Anthony Rizzo ◽

Michael Haffner ◽

Alan Meeker ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Cancer Cell Lines ◽

Telomere Maintenance ◽

Alternative Lengthening Of Telomeres ◽

Prostate Cancer Cell Lines ◽

Maintenance Mechanism ◽

Alternative Lengthening

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Alternative Lengthening of Telomeres and Chromatin Status

Genes ◽

10.3390/genes11010045 ◽

2019 ◽

Vol 11 (1) ◽

pp. 45 ◽

Cited By ~ 1

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.

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Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation

Journal of Neuro-Oncology ◽

10.1007/s11060-020-03394-y ◽

2020 ◽

Vol 147 (1) ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Monica Sofia Ventura Ferreira ◽

Mia Dahl Sørensen ◽

Stefan Pusch ◽

Dagmar Beier ◽

Anne-Sophie Bouillon ◽

...

Keyword(s):

Isocitrate Dehydrogenase ◽

Telomere Maintenance ◽

Alternative Lengthening Of Telomeres ◽

Isocitrate Dehydrogenase 1 ◽

Maintenance Mechanism ◽

Alternative Lengthening

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SLX4IP promotes RAP1 SUMOylation by PIAS1 to coordinate telomere maintenance through NF-κB and Notch signaling

Science Signaling ◽

10.1126/scisignal.abe9613 ◽

2021 ◽

Vol 14 (689) ◽

pp. eabe9613

Author(s):

Nathaniel J. Robinson ◽

Masaru Miyagi ◽

Jessica A. Scarborough ◽

Jacob G. Scott ◽

Derek J. Taylor ◽

...

Keyword(s):

Notch Signaling ◽

Intracellular Signaling ◽

Binding Protein ◽

Telomere Maintenance ◽

Nucleocytoplasmic Shuttling ◽

Iκb Kinase ◽

Alternative Lengthening ◽

Telomere Binding Protein ◽

Sumo Ligase

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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