Alternative Lengthening of Telomeres: Building Bridges To Connect Chromosome Ends

Hoang, Song My; O’Sullivan, Roderick J.

doi:10.1016/j.trecan.2019.12.009

Cited by 51 publications

(56 citation statements)

References 112 publications

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“…Overall, our analyses showed that both TMM pathways might be active in an individual sample, as previously suggested [ 22 , 23 , 24 , 25 , 26 ]. For example, both telomerase and ALT may be activated when the telomeres are considerably shortened [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity

Sung

Lim

Joung

et al. 2020

Cancers

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Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism that extends telomeres in cancer cells. It influences tumorigenesis and patient survival. Despite the clinical significance of ALT in tumors, the manner in which ALT is activated and influences prognostic outcomes in distinct cancer types is unclear. In this work, we profiled distinct telomere maintenance mechanisms (TMMs) using 8953 transcriptomes of 31 different cancer types from The Cancer Genome Atlas (TCGA). Our results demonstrated that approximately 29% of cancer types display high ALT activity with low telomerase activity in the telomere-lengthening group. Among the distinct ALT mechanisms, homologous recombination was frequently observed in sarcoma, adrenocortical carcinoma, and kidney chromophobe. Five cancer types showed a significant difference in survival in the presence of high ALT activity. Sarcoma patients with elevated ALT had unfavorable risks (p < 0.038) coupled with a high expression of TOP2A, suggesting this as a potential drug target. On the contrary, glioblastoma patients had favorable risks (p < 0.02), and showed low levels of antigen-presenting cells. Together, our analyses highlight cancer type-dependent TMM activities and ALT-associated genes as potential therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity

Sung

Lim

Joung

et al. 2020

Cancers

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“…Increased RPA accumulation at telomeres suggested exposure of telomeric ssDNA. TLK2 or total TLK depletion in U-2-OS cells caused increased numbers of ALT-associated Promyelocytic Leukemia (PML) bodies (APBs), membrane-free compartments that co-stain with TRF2 and PML where ALT-dependent telomere recombination takes place ( Figures 2 D, 2E, and S2 D) ( Hoang and O’Sullivan, 2020 ). Additionally, a remarkable increase in PML body intensity suggested ALT-associated telomere clustering ( Figure 2 F) ( Draskovic et al., 2009 ).…”

Section: Resultsmentioning

confidence: 99%

“…Depletion of total ASF1 induces features of alternative lengthening of telomeres (ALT), a telomerase-independent, recombination-based telomere maintenance mechanism used in 10%–15% of tumors ( Hoang and O’Sullivan, 2020 ; O’Sullivan et al., 2014 ). ALT+ tumors are frequently characterized by inactivation of the Alpha thalassemia/mental retardation syndrome X-linked (ATRX)-Death-domain associated protein (DAXX) complex, which controls histone H3.3 deposition and maintenance of pericentromeric and telomeric heterochromatin.…”

Section: Introductionmentioning

confidence: 99%

Tousled-Like Kinases Suppress Innate Immune Signaling Triggered by Alternative Lengthening of Telomeres

et al. 2020

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Summary The Tousled-like kinases 1 and 2 (TLK1/2) control histone deposition through the ASF1 histone chaperone and influence cell cycle progression and genome maintenance, yet the mechanisms underlying TLK-mediated genome stability remain uncertain. Here, we show that TLK loss results in severe chromatin decompaction and altered genome accessibility, particularly affecting heterochromatic regions. Failure to maintain heterochromatin increases spurious transcription of repetitive elements and induces features of alternative lengthening of telomeres (ALT). TLK depletion culminates in a cGAS-STING-TBK1-mediated innate immune response that is independent of replication-stress signaling and attenuated by the depletion of factors required to produce extra-telomeric DNA. Analysis of human cancers reveals that chromosomal instability correlates with high TLK2 and low STING levels in many cohorts. Based on these findings, we propose that high TLK levels contribute to immune evasion in chromosomally unstable and ALT+ cancers.

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“…Telomeres are nucleoprotein complexes that consist of a tandem 5'-TTAGGG-3' sequence and protect the ends of eukaryotic chromosomes, preventing DNA damage response (DDR), end-to-end fusions and genomic instability [1]. Telomeric DNA ranges from 3 to 15 Kb in humans, leaving a G-rich 3'-single-strand extended beyond the complementary chain, usually called the G-overhang [1,2]. To avoid the end-protection problem due to the overhang chain, the G-tail folds into itself, invading the double-stranded telomeric DNA, forming a lasso-like structure called the t-loop [3], which is protected by a six protein complex called shelterin [4], essential for telomere replication and regulation [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…Telomeric DNA ranges from 3 to 15 Kb in humans, leaving a G-rich 3'-single-strand extended beyond the complementary chain, usually called the G-overhang [1,2]. To avoid the end-protection problem due to the overhang chain, the G-tail folds into itself, invading the double-stranded telomeric DNA, forming a lasso-like structure called the t-loop [3], which is protected by a six protein complex called shelterin [4], essential for telomere replication and regulation [2,3]. The shelterin complex is composed of the telomeric repeat binding factors 1 and 2 (TRF1 and TRF2), which interact with the telomeric double-stranded DNA and the protection of telomeres 1 (POT1) that bind to the single-stranded DNA [5].…”

Section: Introductionmentioning

confidence: 99%

TCGA Pan-Cancer Genomic Analysis of Alternative Lengthening of Telomeres (ALT) Related Genes

Armendáriz‐Castillo

López‐Cortés

García-Cárdenas

et al. 2020

Genes

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Telomere 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 switch from a telomerase-dependent mechanism to ALT; in fact, the co-existence between both mechanisms has been observed in some cancers. Although different elements in the ALT pathway are uncovered, some molecular mechanisms are still poorly understood. Therefore, with the aim to identify potential molecular markers for the study of ALT, we combined in silico approaches in a 411 telomere maintenance gene set. As a consequence, we conducted a genomic analysis of these genes in 31 Pan-Cancer Atlas studies from The Cancer Genome Atlas and found 325,936 genomic alterations; from which, we identified 20 genes highly mutated in the cancer studies. Finally, we made a protein-protein interaction network and enrichment analysis to observe the main pathways of these genes and discuss their role in ALT-related processes, like homologous recombination and homology directed repair. Overall, due to the lack of understanding of the molecular mechanisms of ALT cancers, we proposed a group of genes, which after ex vivo validations, could represent new potential therapeutic markers in the study of ALT.

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Alternative Lengthening of Telomeres: Building Bridges To Connect Chromosome Ends

Cited by 51 publications

References 112 publications

Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity

Pan-Cancer Analysis of Alternative Lengthening of Telomere Activity

Tousled-Like Kinases Suppress Innate Immune Signaling Triggered by Alternative Lengthening of Telomeres

TCGA Pan-Cancer Genomic Analysis of Alternative Lengthening of Telomeres (ALT) Related Genes

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