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Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells

ABSTRACT: Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells

PROVIDER: PRJNA885471 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21755611_1.fastq.gz	Fastqsanger.gz
	SRR21755611_2.fastq.gz	Fastqsanger.gz
	SRR21755612_1.fastq.gz	Fastqsanger.gz
	SRR21755612_2.fastq.gz	Fastqsanger.gz
	SRR21755613_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells

Project description:In this study, we used a patient-derived ALT-positive GBM cell line with native SMARCAL1 deficiency to investigate the role of SMARCAL1 in ALT-mediated telomere synthesis and gliomagenesis in vitro and in vivo. Differential gene expression programs associated with tumorigenesis in D06MG xenografts.

2023-01-04 | GSE214466 | GEO

Functional loss of ATRX and telomerase activates Alternative Lengthening of Telomeres (ALT)

Project description:Functional loss of ATRX and telomerase activates Alternative Lengthening of Telomeres (ALT)

| PRJNA531393 | ENA

TCEAL7 Inhibition of c-Myc Activity in Alternative Lengthening of Telomeres Regulates hTERT Expression

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

Functional loss of ATRX and telomerase activates Alternative Lengthening of Telomeres (ALT)

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

Mammalian telomeres reforged with non-telomeric sequences

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

Signalling Inhibition by Ponatinib Disrupts Productive Alternative Lengthening of Telomeres (ALT)

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

Signalling Inhibition by Ponatinib Disrupts Productive Alternative Lengthening of Telomeres (ALT)

2023-02-20 | PXD037501 | Pride

Signalling inhibition by ponatinib disrupts alternative lengthening of telomeres (ALT)

Project description:Signalling inhibition by ponatinib disrupts alternative lengthening of telomeres (ALT)

| PRJNA787207 | ENA

Peroxiredoxin 1 protects telomeres from oxidative damage preserving chromosome ends for extension by telomerase

Project description:With the increase of atmospheric oxygen 2.3 billion years ago, mechanisms evolved to mitigate the toxic effects of oxygen radicals. Telomeres appear particularly susceptible to oxidative damage, which leads to cellular and organismal aging, cancer, cardiac failure and other diseases. Specific mechanisms of telomere protection from oxidative damage and the molecular consequences of the damage have not been described. Here, we identify the antioxidant enzyme peroxiredoxin 1 (PRDX1) enriched in telomeric chromatin in S and G2 phases of the cell cycle during which telomeres become replicated. PRDX1 depletion leads to oxidative damage of telomeric DNA without affecting the bulk of genomic DNA. The oxidized nucleotide 8-oxo-2’deoxyguanosine-5’-triphosphate (8oxodGTP) can be incorporated by telomerase into telomeric repeats but it mediates premature chain termination when incorporated as first G in the telomeric 5’-TTAGGG-3’ sequence. In dependency of the alignment position within the telomerase RNA template, terminus 8oxoG containing DNA substrates also completely block extension by telomerase. We propose two major mechanisms by which PRDX1 counteracts telomere damage and aging. In safeguarding telomeres from oxygen radicals, PRDX1 prevents DNA damage, telomere replication defects and mutations that will perturb recognition of telomeric DNA by shelterin components. In preventing modification of the telomeric DNA substrate and the dNTP pool, PRDX1 preserves telomeres for elongation by telomerase.

2016-12-07 | PXD002626 | Pride

Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres

Project description:In our previous study, mice with pulmonary fibrosis induced by a bleomycin insult in the context of short telomeres develop pulmonary fibrosis. By using AAV9 vectors carrying the telomerase Tert gene to treat those mice, we explore the possibility of telomerase gene therapy as a possible treatment for IPF patients carrying short telomeres. To further understand gene expression changes undergoing in ATII cells upon telomerase activation, we isolated ATII cells from pulmonary fibrosis Tert-treated and empty vector-treated lungs at 1 week after AAV9 inoculation by FACS.

2018-01-22 | GSE93869 | GEO

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