Rapid and reversible suppression of ALT by DAXX in osteosarcoma cells

Yost, Kathryn E.; Soper, Sarah F. Clatterbuck; Walker, Robert L.; Pineda, Marbin; Zhu, Yuelin J.; Ester, Corbin D.; Showman, Soyeon A.; Roschke, Anna V.; Waterfall, Joshua J.; Meltzer, Paul S.

doi:10.1038/s41598-019-41058-8

Cited by 35 publications

(26 citation statements)

References 40 publications

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“…ALT is usually detected by telomere-specific fluorescence in situ hybridization, APB immunofluorescence, and ALT-associated molecule detection assays [157,158]. Mutations in the genes encoding for the α-thalassemia/mental retardation syndrome X-linked protein (ATRX) and the death domain-associated protein (DAXX) have been associated with ALT-positive tumors [159]. ATRX, together with DAXX, function as a chromatin remodeling complex that facilitates the deposition of histone variant H3.3 at the telomeres [160].…”

Section: Alternative Lengthening Of Telomeresmentioning

confidence: 99%

“…ATRX loss compromises the cell cycle regulation of TERRA and leads to the persistent association of replication protein A (RPA) with telomeres, resulting in a recombinant nucleoprotein structure [162]. ALT is observed at a high frequency in tumors of the central nervous system, peripheral nervous system, and sarcoma, but rare in carcinomas [159,163]. ALT is a telomerase-independent mechanism that occurs via homologous recombination to maintain telomere length.…”

Section: Alternative Lengthening Of Telomeresmentioning

confidence: 99%

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Telomeres and Telomere Length: A General Overview

Srinivas

Rachakonda

Kumar

2020

Cancers

190

130

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Telomeres are highly conserved tandem nucleotide repeats that include proximal double-stranded and distal single-stranded regions that in complex with shelterin proteins afford protection at chromosomal ends to maintain genomic integrity. Due to the inherent limitations of DNA replication and telomerase suppression in most somatic cells, telomeres undergo age-dependent incremental attrition. Short or dysfunctional telomeres are recognized as DNA double-stranded breaks, triggering cells to undergo replicative senescence. Telomere shortening, therefore, acts as a counting mechanism that drives replicative senescence by limiting the mitotic potential of cells. Telomere length, a complex hereditary trait, is associated with aging and age-related diseases. Epidemiological data, in general, support an association with varying magnitudes between constitutive telomere length and several disorders, including cancers. Telomere attrition is also influenced by oxidative damage and replicative stress caused by genetic, epigenetic, and environmental factors. Several single nucleotide polymorphisms at different loci, identified through genome-wide association studies, influence inter-individual variation in telomere length. In addition to genetic factors, environmental factors also influence telomere length during growth and development. Telomeres hold potential as biomarkers that reflect the genetic predisposition together with the impact of environmental conditions and as targets for anti-cancer therapies.

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Section: Alternative Lengthening Of Telomeresmentioning

confidence: 99%

Section: Alternative Lengthening Of Telomeresmentioning

confidence: 99%

Telomeres and Telomere Length: A General Overview

Srinivas

Rachakonda

Kumar

2020

Cancers

190

130

View full text Add to dashboard Cite

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“…Genetic alterations in the histone chaperone and ATRX binding partner DAXX (death domain associated protein) have also been shown to result in ALT due to a failure to localise ATRX to PML bodies [34]. In addition genetic alterations in tumour protein 53 (TP53) and retinoblastoma 1 (RB1) have also been associated with ALT [13] however the mechanistic basis for these associations is currently unknown.…”

Section: Biology Of Telomere Maintenancementioning

confidence: 99%

Novel therapeutic strategies targeting telomere maintenance mechanisms in high-risk neuroblastoma

George

Parmar

Lorenzi

et al. 2020

J Exp Clin Cancer Res

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The majority of high-risk neuroblastomas can be divided into three distinct molecular subgroups defined by the presence of MYCN amplification, upstream TERT rearrangements or alternative lengthening of telomeres (ALT). The common defining feature of all three subgroups is altered telomere maintenance; MYCN amplification and upstream TERT rearrangements drive high levels of telomerase expression whereas ALT is a telomerase independent telomere maintenance mechanism. As all three telomere maintenance mechanisms are independently associated with poor outcomes, the development of strategies to selectively target either telomerase expressing or ALT cells holds great promise as a therapeutic approach that is applicable to the majority of children with aggressive disease. Here we summarise the biology of telomere maintenance and the molecular drivers of aggressive neuroblastoma before describing the most promising therapeutic strategies to target both telomerase expressing and ALT cancers. For telomerase-expressing neuroblastoma the most promising targeted agent to date is 6-thio-2′-deoxyguanosine, however clinical development of this agent is required. In osteosarcoma cell lines with ALT, selective sensitivity to ATR inhibition has been reported. However, we present data showing that in fact ALT neuroblastoma cells are more resistant to the clinical ATR inhibitor AZD6738 compared to other neuroblastoma subtypes. More recently a number of additional candidate compounds have been shown to show selectivity for ALT cancers, such as Tetra-Pt (bpy), a compound targeting the telomeric G-quadruplex and pifithrin-α, a putative p53 inhibitor. Further pre-clinical evaluation of these compounds in neuroblastoma models is warranted. In summary, telomere maintenance targeting strategies offer a significant opportunity to develop effective new therapies, applicable to a large proportion of children with high-risk neuroblastoma. In parallel to clinical development, more pre-clinical research specifically for neuroblastoma is urgently needed, if we are to improve survival for this common poor outcome tumour of childhood.

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“…Recent work has improved our understanding of the underlying mechanism of ALT, however, despite this, it is still not clear as to the exact process by which ALT development occurs. Due to the near universal loss of the SWI/SNF protein ATRX in ALT cancer, and the ability of ATRX to suppress markers of ALT in a DAXX dependent manner, it would appear that loss of ATRX is a key factor in the development of ALT (27)(28)(29). Indeed, one recent study showed that, in certain cell lines, markers of ALT could be triggered upon loss of ATRX alone (28).…”

Section: The Role Of Atrx In Alt Developmentmentioning

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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Rapid and reversible suppression of ALT by DAXX in osteosarcoma cells

Cited by 35 publications

References 40 publications

Telomeres and Telomere Length: A General Overview

Telomeres and Telomere Length: A General Overview

Novel therapeutic strategies targeting telomere maintenance mechanisms in high-risk neuroblastoma

Alternative Lengthening of Telomeres in Pediatric Cancer: Mechanisms to Therapies

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