Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE214466 | GEO | 2023/01/04
REPOSITORIES: GEO
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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: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) 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:Replicative senescence forms a major barrier to tumor progression. Cancer cells bypass this by using one of the two known telomere maintenance mechanisms: telomerase or the recombination-based alternative lengthening of telomeres (ALT) mechanism. The molecular details of ALT are currently poorly understood. We have previously shown that telomerase is actively repressed through complex networks of kinase, gene expression, and chromatin regulation. In this study, we aimed to gain further understanding of the role of kinases in the regulation of telomerase expression in ALT cells. Using a whole human kinome siRNA screen, we highlighted 106 kinases whose expression is linked to hTERT promoter activity. Network modeling of transcriptional regulation implicated c-Myc as a key regulator of the 106 kinase hits. Given our previous observations of lower c-Myc activity in ALT cells, we further explored its potential to regulate telomerase expression in ALT. We found increased c-Myc binding at the hTERT promoter in telomerase-positive compared with ALT cells, although no expression differences in c-Myc, Mad, or Max were observed between ALT and telomerase-positive cells that could explain decreased c-Myc activity in ALT. Instead, we found increased expression of the c-Myc competitive inhibitor TCEAL7 in ALT cells and tumors and that alteration of TCEAL7 expression levels in ALT and telomerase-positive cells affects hTERT expression. Lower c-Myc activity in ALT may therefore be obtained through TCEAL7 regulation. Thus, TCEAL7 may present an interesting novel target for cancer therapy, which warrants further investigation.
2010-05-04 | GSE17118 | GEO
Project description:Observing the gene expression of ATRX, DAXX, H3F3A, SMARCAL1, SLX4IP and TERT in 7 patient derived osteosarcoma xenograft samples (Houghton et al., 2007) which are using the Alternative Lengthening of Telomere (ALT) pathway.
2019-09-01 | GSE124768 | GEO
Project description:Telomere is a highly refined system for maintaining the stability of linear chromosomes. Most telomeres rely on simple repetitive sequences and telomerase enzymes, but in some species or telomerase-defective situations, alternative telomere lengthening (ALT) mechanism is utilized to protect chromosomal ends. Telomere loss can induce telomere recombination by which specific sequences can be recruited into telomeres. However, canonical telomeric repeat-based telomeres have been found in mammals. Here, we show that mammalian telomeres can also be completely reconstituted using a non-telomeric unique sequence. We found that a specific subtelomeric element, named as mouse template for ALT (mTALT), is utilized for repairing telomeric DNA damage and composing new telomeric sequences in mouse embryonic stem cells. We found a high-level of non-coding mTALT transcript despite the heterochromatic nature of mTALT-based telomere. After ALT activation, the increased HMGN1, a non-histone chromosomal protein, contributed to maintaining telomere stability by regulating telomeric transcriptions. Our findings reveal novel molecular features of potential telomeric sequences which can reconstitute telomeres during cancer formation and evolution.
2020-07-17 | MSV000085772 | MassIVE
Project description:Telomere maintenance is indispensable for perpetuated cell division, but telomeres are not necessarily composed of a fixed sequence. Here we report the establishment of a model for alternative lengthening of telomeres (ALT) in mouse embryonic stem cells (mESCs) in which telomeres are reconstructed with an internal ALT template. Longitudinal whole-genome analyses of ALT mESCs showed that pre-amplification of the template into a telomeric region was a prerequisite for ALT activation, and that extensive copy number variations became concentrated in subtelomeric regions. Epigenomic analysis revealed the heterochromatic structure of the ALT telomeres, except for an insulator region within the ALT template. Quantitative proteomics followed by single-cell RNA-sequencing and functional assays revealed that HMGN1 protected new telomeres by regulating telomere repeat-containing RNA transcription and R loop formation in ALT mESCs. These findings implicate an evolutionarily conserved ALT mechanism driven by an internal template and provide a molecular basis underlying telomere evolution.
2020-12-30 | GSE147914 | GEO
Project description:Telomere maintenance is indispensable for perpetuated cell division, but telomeres are not necessarily composed of a fixed sequence. Here we report the establishment of a model for alternative lengthening of telomeres (ALT) in mouse embryonic stem cells (mESCs) in which telomeres are reconstructed with an internal ALT template. Longitudinal whole-genome analyses of ALT mESCs showed that pre-amplification of the template into a telomeric region was a prerequisite for ALT activation, and that extensive copy number variations became concentrated in subtelomeric regions. Epigenomic analysis revealed the heterochromatic structure of the ALT telomeres, except for an insulator region within the ALT template. Quantitative proteomics followed by single-cell RNA-sequencing and functional assays revealed that HMGN1 protected new telomeres by regulating telomere repeat-containing RNA transcription and R loop formation in ALT mESCs. These findings implicate an evolutionarily conserved ALT mechanism driven by an internal template and provide a molecular basis underlying telomere evolution.
2020-12-30 | GSE147915 | GEO
Project description:Telomere maintenance is indispensable for perpetuated cell division, but telomeres are not necessarily composed of a fixed sequence. Here we report the establishment of a model for alternative lengthening of telomeres (ALT) in mouse embryonic stem cells (mESCs) in which telomeres are reconstructed with an internal ALT template. Longitudinal whole-genome analyses of ALT mESCs showed that pre-amplification of the template into a telomeric region was a prerequisite for ALT activation, and that extensive copy number variations became concentrated in subtelomeric regions. Epigenomic analysis revealed the heterochromatic structure of the ALT telomeres, except for an insulator region within the ALT template. Quantitative proteomics followed by single-cell RNA-sequencing and functional assays revealed that HMGN1 protected new telomeres by regulating telomere repeat-containing RNA transcription and R loop formation in ALT mESCs. These findings implicate an evolutionarily conserved ALT mechanism driven by an internal template and provide a molecular basis underlying telomere evolution.
2020-12-30 | GSE147913 | GEO
Project description:Telomere maintenance is indispensable for perpetuated cell division, but telomeres are not necessarily composed of a fixed sequence. Here we report the establishment of a model for alternative lengthening of telomeres (ALT) in mouse embryonic stem cells (mESCs) in which telomeres are reconstructed with an internal ALT template. Longitudinal whole-genome analyses of ALT mESCs showed that pre-amplification of the template into a telomeric region was a prerequisite for ALT activation, and that extensive copy number variations became concentrated in subtelomeric regions. Epigenomic analysis revealed the heterochromatic structure of the ALT telomeres, except for an insulator region within the ALT template. Quantitative proteomics followed by single-cell RNA-sequencing and functional assays revealed that HMGN1 protected new telomeres by regulating telomere repeat-containing RNA transcription and R loop formation in ALT mESCs. These findings implicate an evolutionarily conserved ALT mechanism driven by an internal template and provide a molecular basis underlying telomere evolution.
2020-12-30 | GSE160487 | GEO