Ontology highlight
ABSTRACT:
PROVIDER: PRJNA796771 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17604000_1.fastq.gz | Fastqsanger.gz | |||
| SRR17604000_2.fastq.gz | Fastqsanger.gz | |||
| SRR17604001_1.fastq.gz | Fastqsanger.gz | |||
| SRR17604001_2.fastq.gz | Fastqsanger.gz | |||
| SRR17604002_1.fastq.gz | Fastqsanger.gz |
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Project description:We sequenced and characterised inter-chromosomal and intra-chromosomal telomere fusions amplified from crisis-stage MCR5HPVE6E7 fibroblasts and DNA repair-compromised HCT116 cell lines nucleofected with plasmids encoding TALEN pairs to induce targeted cleavage at the 17p telomere.
2016-02-24 | E-MTAB-3811 | biostudies-arrayexpress
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:The goal of this experiment is to determine the effect of ATRX depletion on telomeric chromatin compaction. We adapted the ATAC-seq to quantify telomere chromatin accessibility. By scoring the ratio of sequence reads that contained 3 - 12 tandem telomeric repeats over the total number of reads in wild-type and ATRX deplted cells, our analysis revealed that CRISPR/Cas9-mediated ATRX depletion induces a progressive telomere de-compaction.
2019-08-26 | GSE130640 | GEO
Project description:ATRX is a chromatin remodelling factor found at a wide range of tandemly repeated sequences including telomeres (TTAGGG)n. Acquired mutations in ATRX are found in nearly all tumours which maintain their telomeres via the alternative lengthening of telomere (ALT) pathway and ATRX is known to suppress this pathway. Here we show that recruitment of ATRX to telomeric repeats is dependent on their number, their orientation and, critically, on their transcription. Importantly, the transcribed telomeric repeats form RNA-DNA hybrids (R-loops) whose abundance correlates with the recruitment of ATRX. Here we show loss of ATRX is also associated with an increase in R-loop formation. These findings suggest that the presence of ATRX at telomeres may reflect a central role in suppressing deleterious DNA secondary structures which form at transcribed telomeric repeats, and this may account for the increases in DNA damage, stalling of replication and homology directed repair previously observed upon loss of ATRX function.
2017-09-08 | GSE96768 | GEO
Project description:The synthesis of poly(ADP-ribose) (PAR) reconfigures the local environment and recruits repair complexes to damaged chromatin. The degradation of PAR by PARG is essential for progression and completion of DNA repair. Here, we show that inhibition of PARG disrupts homology-directed repair (HDR) mechanisms that underpin alternative telomere lengthening (ALT). By proteomics, we uncovered a novel role for PARylation in regulating the chromatin assembly factor, HIRA in ALT cancer cells. We show that HIRA is enriched at telomeres during G2 phase and is indispensable for histone H3.3 deposition and telomere DNA synthesis. Depletion of HIRA elicits systemic death of ALT cancer cells was mitigated by re-expression of ATRX protein that is frequently inactivated in ALT tumors. We propose that PARylation enables HIRA to fulfill its essential role in the adaptive response due to ATRX deficiency that pervades ALT cancers.
2020-10-12 | PXD020243 | Pride
Project description:The Alternative Lengthening of Telomeres (ALT) pathway stimulates telomere elongation and prevents cellular senescence in approximately 60% of osteosarcoma. While the precise mechanisms underlying the ALT pathway are unclear, mutations in the chromatin remodeling protein ATRX, histone chaperone DAXX, and the histone variant H3.3, correlate with ALT status. ATRX and DAXX facilitate deposition of the histone variant H3.3 within heterochromatic regions including the telomere suggesting that loss of ATRX, DAXX, and/or H3.3 lead to defects in heterochromatin maintenance at telomeres, ultimately contributing to ALT activity. Previous studies have detected genetic mutations in ATRX, DAXX, and H3.3 in ALT cell lines and tumor samples. However, a subset of ALT samples show loss of ATRX or DAXX protein expression or localization without evidence of genetic alterations, indicating a role for other defects in ATRX/DAXX/H3.3 function. Here, using Next Generation Sequencing, we identified a novel gene fusion event between DAXX and the kinesin motor protein, KIFC3, which leads to the translation of a chimeric DAXX-KIFC3 fusion protein. Here, we demonstrate that the fusion of KIFC3 to DAXX leads to defects in DAXX function and likely perpetuates ALT activity. These data highlight a previously unrecognized mechanism of DAXX inactivation in ALT positive osteosarcoma and provide rationale for thorough and comprehensive analyses of ATRX/DAXX/H3.3 proteins in ALT positive cancers.
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Project description:DAXX and ATRX are tumor suppressor proteins that form a complex with histone H3.3 chaperone and are frequently mutated in cancers with the alternative lengthening of telomeres (ALT), such as pediatric glioblastoma. Rapid loss of function of either DAXX or ATRX are not by themselves sufficient to induce the ALT phenotype. However, cells lacking DAXX or ATRX can be readily selected for ALT-like features. Here, we show that a key feature of ALT selected DAXX and ATRX null glioblastoma cells is the attenuation of p53 function. RNA-seq analysis of DAXX or ATRX null U87 glioblastoma cells with ALT-like features revealed that p53 pathway is among perturbed. ALT-selected DAXX and ATRX-null cells had aberrant response to DNA damaging agent etoposide. Both DAXX and ATRX-null ALT cells showed a loss of p53 binding at a subset of response elements. Complementation of DAXX null cells with wt DAXX rescued p53 binding and transcription, while the tumor associated mutation L130R, that disrupts ATRX binding, was incapable of rescuing p53 chromatin binding. We show that histone H3.3 binding is reduced in DAXX-null cells especially at subtelomeric p53 binding sites and telomere repeats. These findings indicate that DAXX and ATRX function to enable p53 chromatin binding through modulation of histone H3.3 binding, especially at sub-telomeric sites.
2022-07-19 | GSE186442 | GEO
Project description:DAXX and ATRX are tumor suppressor proteins that form a complex with histone H3.3 chaperone and are frequently mutated in cancers with the alternative lengthening of telomeres (ALT), such as pediatric glioblastoma. Rapid loss of function of either DAXX or ATRX are not by themselves sufficient to induce the ALT phenotype. However, cells lacking DAXX or ATRX can be readily selected for ALT-like features. Here, we show that a key feature of ALT selected DAXX and ATRX null glioblastoma cells is the attenuation of p53 function. RNA-seq analysis of DAXX or ATRX null U87 glioblastoma cells with ALT-like features revealed that p53 pathway is among perturbed. ALT-selected DAXX and ATRX-null cells had aberrant response to DNA damaging agent etoposide. Both DAXX and ATRX-null ALT cells showed a loss of p53 binding at a subset of response elements. Complementation of DAXX null cells with wt DAXX rescued p53 binding and transcription, while the tumor associated mutation L130R, that disrupts ATRX binding, was incapable of rescuing p53 chromatin binding. We show that histone H3.3 binding is reduced in DAXX-null cells especially at subtelomeric p53 binding sites and telomere repeats. These findings indicate that DAXX and ATRX function to enable p53 chromatin binding through modulation of histone H3.3 binding, especially at sub-telomeric sites.
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Project description:Telomere integrity is critical for embryonic development and core telomere-binding proteins such as TIN2 are key to maintaining telomere stability. Here we report that homozygous Tin2S341X resulted in embryonic lethality in mice and reduced expression of Tin2 in the derived mouse embryonic stem cells (mESCs). Homozygous mutant mESCs were able to self-renew and remain undifferentiated but displayed many phenotypes associated with alternative lengthening of telomeres (ALT), including excessively long and heterogeneous telomeres, increased ALT-associated PML bodies, and unstable chromosomal ends. These cells also showed upregulation of Zscan4 expression and elevated targeting of DAXX/ATRX and H3K9me3 marks on telomeres. Furthermore, the mutant mESCs were impeded in their differentiation capacity. Upon differentiation, DAXX/ATRX and PML bodies disassociated from telomeres in these cells, where elevated DNA damage was also apparent. Our results reveal differential responses to telomere dysfunction in mESCs versus differentiated cells and highlight the critical role of TIN2 in embryonic development.
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