Functional loss of ATRX and telomerase activates Alternative Lengthening of Telomeres (ALT)
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PROVIDER: PRJNA531393 | ENA |
REPOSITORIES: ENA
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Project description:The presence of ALT is strongly associated with recurrent cancer-specific somatic inactivating mutations in the ATRX-DAXX chromatin remodeling complex. Here, we generate an ALT-positive adenocarcinoma cell line following functional inactivation of ATRX and telomerase in a telomerase-positive carcinoma cell line.
2019-09-25 | GSE129448 | GEO
Project description:DNA microarrays were used to define the transcriptional profiles of tumor samples to compare 12 high-grade pediatric osteosarcoma tumor samples on their ALT and ATRX status.
2022-07-12 | E-MTAB-11743 | biostudies-arrayexpress
Project description:Alternative lengthening of telomeres (ALT) supports telomere maintenance and replicative immortality in around 10-15% of cancers, thus representing a compelling target for therapy.To identify anti-cancer drugs that can be repurposed as ALT-centered therapies, we performed for a compound library screen on isogenic cell lines that rely either on telomerase or ALT mechanisms. We validated candidates on a panel of ALT- vs. telomerase-positive sarcoma cells and assessed levels of extrachromosomal telomeric C-circles after drug treatment, as a bona fide marker of ALT activity. We identified a receptor tyrosine kinase inhibitor ponatinib that deregulated ALT mechanisms, increased telomeric replicative stress and induced telomeric dysfunction in ALT cells. Using a model of ALT sarcoma xenografts, we found that ponatinib targeted ALT-positive cells and mitigated telomere elongation in these tumors. To identify the mode of action of ponatinib on ALT, we performed RNA-sequencing and quantitative proteomic and phosphoproteomic analyses, and shortlisted candidates to test the effect of their loss on telomeric C-circle levels. We identified an ABL1-JNK-JUN signalling circuit to be inhibited by ponatinib and to have a role in suppressing extrachromosomal telomeric C-circle formation. Furthermore, transcriptome and interactome analyses of JUN suggested a role of JUN in DNA damage repair pathways, independently of its capacity as a transcription factor. These results were corroborated by new synergistic drug interactions between ponatinib and either DNA synthesis or repair inhibitors such as triciribine and KU-60019, respectively. Overall, we identified a novel signalling pathway impacting ALT which can be targeted by a clinically approved kinase inhibitor.
2023-02-20 | PXD037501 | Pride
Project description:Alternative lengthening of telomeres (ALT) supports telomere maintenance and replicative immortality in around 10-15% of cancers, thus representing a compelling target for therapy.To identify anti-cancer drugs that can be repurposed as ALT-centered therapies, we performed for a compound library screen on isogenic cell lines that rely either on telomerase or ALT mechanisms. We validated candidates on a panel of ALT- vs. telomerase-positive sarcoma cells and assessed levels of extrachromosomal telomeric C-circles after drug treatment, as a bona fide marker of ALT activity. We identified a receptor tyrosine kinase inhibitor ponatinib that deregulated ALT mechanisms, increased telomeric replicative stress and induced telomeric dysfunction in ALT cells. Using a model of ALT sarcoma xenografts, we found that ponatinib targeted ALT-positive cells and mitigated telomere elongation in these tumors. To identify the mode of action of ponatinib on ALT, we performed RNA-sequencing and quantitative proteomic and phosphoproteomic analyses, and shortlisted candidates to test the effect of their loss on telomeric C-circle levels. We identified an ABL1-JNK-JUN signalling circuit to be inhibited by ponatinib and to have a role in suppressing extrachromosomal telomeric C-circle formation. Furthermore, transcriptome and interactome analyses of JUN suggested a role of JUN in DNA damage repair pathways, independently of its capacity as a transcription factor. These results were corroborated by new synergistic drug interactions between ponatinib and either DNA synthesis or repair inhibitors such as triciribine and KU-60019, respectively. Overall, we identified a novel signalling pathway impacting ALT which can be targeted by a clinically approved kinase inhibitor.
2022-03-14 | PXD032188 | Pride
Project description:Alternative Lengthening of Telomeres (ALT) is an aberrant DNA recombination pathway which grants replicative immortality to approximately 10% of all cancers. Despite this high prevalence of ALT in cancer, the mechanism and genetics by which cells activate this pathway remain incompletely understood. A major challenge in dissecting the events that initiate ALT is the extremely low frequency of ALT induction in human cell systems. Guided by the genetic lesions that have been associated with ALT from cancer sequencing studies, we genetically engineered primary human pluripotent stem cells to deterministically induce ALT upon differentiation. Using this genetically defined system, we demonstrate that disruption of the p53 and Rb pathways in combination with ATRX loss-of-function is sufficient to induce all hallmarks of ALT and results in functional immortalization in a cell type-specific manner. We further demonstrate that ALT can be induced in the presence of telomerase, is neither dependent on telomere shortening nor crisis, but is rather driven by continuous telomere instability triggered by the induction of differentiation in ATRX-deficient stem cells.
2023-02-21 | GSE212809 | GEO
Project description:<p>Many tumors maintain chromosome ends through a telomerase-independent, homologous recombination based mechanism called alternative lengthening of telomeres (ALT). While ALT occurs in only a subset of tumors, it is strongly associated with mutations in the genes encoding components of the histone H3.3 chaperone complex, ATRX and DAXX. To date the mechanistic role of ATRX and particularly DAXX mutations in potentiating ALT remains poorly understood. We identify an osteosarcoma cell line, G292, with a unique chromosomal translocation resulting in loss of DAXX function, while retaining functional ATRX. Using this distinctive resource, we demonstrate that introduction of wild type DAXX suppresses the ALT phenotype and restores localization of the ATRX/DAXX complex to PML bodies. This provides the first direct molecular evidence that ongoing DAXX deficiency is essential for maintenance of the ALT phenotype and highlights the potential for therapeutic targeting of this oncogenic pathway.</p>
| phs001495 | dbGaP
Project description:Alterations to chromatin modifiers, such as the inactivating mutations in the ATRX-DAXX chromatin remodeling/histone H3.3 deposition complex, are implicated as drivers of the cancer-specific Alternative Lengthening of Telomeres (ALT) pathway. Prior studies revealed that HIRA adapts to compensate for ATRX-DAXX loss to sustain ALT cancer cell survival. However, the specific mechanisms underlying HIRA’s ability to rescue telomeres from the consequences of ATRX-DAXX loss remain unclear. Here, using ATAC-seq and CUT&RUN, we demonstrate that HIRA-mediated deposition of new H3.3 is essential to maintain chromatin accessibility and to prevent the detrimental accumulation of nucleosome-free single-stranded DNA (ssDNA) at telomeres in ATRX-deficient ALT cancer cells. We provide evidence that the timely deposition of new H3.3 by HIRA and interacting partners UBN1 and UBN2 is crucial to prevent unwarranted TERRA R-loop formation and transcription-replication conflicts (TRCs) at telomeres. Furthermore, we determined that the delivery of H3.3 to telomeric chromatin by HIRA may link the phosphorylation of an H3.3-specific amino acid, serine 31, by Chk1 with mechanisms that promote productive ALT. Therefore, these studies identify a role for HIRA-mediated histone H3.3 deposition in TERRA R-loop homeostasis that we propose is essential for ensuring the survival of ALT cancer cells where the ATRX-DAXX complex is activated.
2024-10-21 | GSE269268 | GEO
Project description:Alterations to chromatin modifiers, such as the inactivating mutations in the ATRX-DAXX chromatin remodeling/histone H3.3 deposition complex, are implicated as drivers of the cancer-specific Alternative Lengthening of Telomeres (ALT) pathway. Prior studies revealed that HIRA adapts to compensate for ATRX-DAXX loss to sustain ALT cancer cell survival. However, the specific mechanisms underlying HIRA’s ability to rescue telomeres from the consequences of ATRX-DAXX loss remain unclear. Here, using ATAC-seq and CUT&RUN, we demonstrate that HIRA-mediated deposition of new H3.3 is essential to maintain chromatin accessibility and to prevent the detrimental accumulation of nucleosome-free single-stranded DNA (ssDNA) at telomeres in ATRX-deficient ALT cancer cells. We provide evidence that the timely deposition of new H3.3 by HIRA and interacting partners UBN1 and UBN2 is crucial to prevent unwarranted TERRA R-loop formation and transcription-replication conflicts (TRCs) at telomeres. Furthermore, we determined that the delivery of H3.3 to telomeric chromatin by HIRA may link the phosphorylation of an H3.3-specific amino acid, serine 31, by Chk1 with mechanisms that promote productive ALT. Therefore, these studies identify a role for HIRA-mediated histone H3.3 deposition in TERRA R-loop homeostasis that we propose is essential for ensuring the survival of ALT cancer cells where the ATRX-DAXX complex is activated.
2024-10-21 | GSE269261 | GEO
Project description:Signalling inhibition by ponatinib disrupts alternative lengthening of telomeres (ALT)
| PRJNA787207 | ENA
Project description:The up-regulation of a telomere maintenance mechanism (TMM) is an essential step in cancer progression to escape dysfunctional telomeres, senescence and apoptosis. Paediatric brain tumors frequently exhibit Alternative Lengthening of Telomere (ALT) as active TMM, but the mechanisms involved in the induction of ALT in brain tumor cells are not clear. Here, we report a model of juvenile zebrafish brain tumor that progressively develops ALT. We discovered that reduced expression of tert and increase in Terra expression precedes ALT development. Additionally, tumors show persistent telomeric DNA damage and loss of heterochromatin marks. Comparative analysis of gene expression after the rescue of ALT with telomerase and analysis of telomerase positive paediatric brain cancers showed normalization of telomeric heterochromatin and maintenance of telomere length, with reduced expression of genes of the pre-replicative complex as hallmark. Thus our study identifies telomere maintenance mechanisms as major drivers of DNA replication and chromatin status at telomeres in brain cancers.
2022-07-01 | GSE134135 | GEO