Alternative lengthening of telomeres can be maintained by preferential elongation of lagging strands

Min, Jaewon; Wright, Woodring E.; Shay, Jerry W.

doi:10.1093/nar/gkw1295

Cited by 41 publications

(50 citation statements)

References 57 publications

(90 reference statements)

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“…Moreover, in mice, ATRX has been shown to reduce HP1α and lead to chromatin decompaction [66]. Finally, a recent study has shown that preferential elongation of overhangs at the lagging chromatids promotes ALT, and ATRX was shown to partially suppress this process [69]. Despite the frequent mutation rate of ATRX/DAXX, its worth to mention that their mutations alone are not enough to initiate ALT, as has been shown for SV-40 hTERT immortalized cell lines [44].…”

Section: The Role Of Atrx and Daxxmentioning

confidence: 96%

“…The violet branch involves factors that are associated with heterochromatic state or stability of telemetric DNA ends. While ATRX/DAXX genes are mutated in the majority of ALT cells, the depletion of wild variants also promotes ALT activity [69]. We did not have genome variant data for the studied samples, and thus have considered higher expressions of these genes to have inhibitory effects on ALT.…”

Section: The Alt Pathwaymentioning

confidence: 99%

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A transcriptome and literature guided algorithm for reconstruction of pathways to assess activity of telomere maintenance mechanisms

Nersisyan

Arakelyan

2017

Preprint

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Activation of telomere maintenance mechanisms (TMMs) is a crucial factor for indefinite proliferation of cancer cells. The most common TMM is based on the action of telomerase, but in some cancers telomeres are elongated via homologous recombination based alternative mechanism (ALT). Despite their importance, little is known about TMM regulation and factors responsible for TMM phenotype choice in different cells. Currently, many studies address the involvement of few genes in TMMs, but a consensus unified picture of the full process is missing.We have developed a computational biology framework combining knowledge-and data-driven approaches to aid in understanding of TMMs. It is based on a greedy algorithm with three core modules: (1) knowledge-based construction/modification of molecular pathways for telomerase-dependent and alternative TMMs, (2) coupled with gene expression data-based validation with an in-house pathway signal flow (PSF) algorithm, and (3) iteration of these two coupled steps until converging at pathway topologies that best reflect state of the art knowledge and are in maximum accordance with the data. We have used gene expression data derived from cell lines and tumor tissues and have performed extensive literature search and multiple cycles of greedy iterations until reaching TMM assessment accuracy of 100% and 77%, respectively.Availability of TMM pathways that best reflect recent knowledge and data will facilitate better understanding of TMM processes. As novel experimental findings in TMM biology emerge, and new datasets are generated, our approach may be used to further expand/improve the pathways, possibly allowing for making distinctions not only between telomerase-dependent and ALT TMMs, but also among their different subtypes. Moreover, this method may be used

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Section: The Role Of Atrx and Daxxmentioning

confidence: 96%

Section: The Alt Pathwaymentioning

confidence: 99%

A transcriptome and literature guided algorithm for reconstruction of pathways to assess activity of telomere maintenance mechanisms

Nersisyan

Arakelyan

2017

Preprint

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“…ALT telomeres are highly heterogeneous in length, but the average length is about double that of most somatic cells where telomeres are maintained by telomerase [37]. ALT telomeres can also display excessively long single-strand G-rich overhangs, with the longest reported measuring 400 nucleotides [38], more than twice the reported overhang length in telomerase positive cells. There is also evidence that ALT positive cells possess highly unusual telomeric structures not found in telomerase positive cell lines.…”

Section: Phenotypes Specific To Altmentioning

confidence: 99%

ALT: A Multi-Faceted Phenomenon

Sommer

Royle

2020

Genes

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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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“…Telomere maintenance in ALT is thought to be mediated by a pathway referred to as break induced replication (BIR), with a preference for lagging strand synthesis (57). Seminal work in the field from Dilley et al implicated a primary three protein axis of POLD3, PCNA, and RAD52 in the mechanism of ALT telomere extension.…”

Section: Break Induced Replication Drives Alt Telomere Synthesismentioning

confidence: 99%

Alternative Lengthening of Telomeres in Pediatric Cancer: Mechanisms to Therapies

et al. 2020

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Achieving replicative immortality is a crucial step in tumorigenesis and requires both bypassing cell cycle checkpoints and the extension of telomeres, sequences that protect the distal ends of chromosomes during replication. In the majority of cancers this is achieved through the enzyme telomerase, however a subset of cancers instead utilize a telomerase-independent mechanism of telomere elongation-the Alternative Lengthening of Telomeres (ALT) pathway. Recent work has aimed to decipher the exact mechanism that underlies this pathway. To this end, this pathway has now been shown to extend telomeres through exploitation of DNA repair machinery in a unique process that may present a number of druggable targets. The identification of such targets, and the subsequent development or repurposing of therapies to these targets may be crucial to improving the prognosis for many ALT-positive cancers, wherein mean survival is lower than non-ALT counterparts and the cancers themselves are particularly unresponsive to standard of care therapies. In this review we summarize the recent identification of many aspects of the ALT pathway, and the therapies that may be employed to exploit these new targets.

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Alternative lengthening of telomeres can be maintained by preferential elongation of lagging strands

Cited by 41 publications

References 57 publications

A transcriptome and literature guided algorithm for reconstruction of pathways to assess activity of telomere maintenance mechanisms

A transcriptome and literature guided algorithm for reconstruction of pathways to assess activity of telomere maintenance mechanisms

ALT: A Multi-Faceted Phenomenon

Alternative Lengthening of Telomeres in Pediatric Cancer: Mechanisms to Therapies

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