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NR2C/F orphan receptors induce telomere-genome rearrangements in ALT

ABSTRACT: Most sarcomas have complex karyotype and are characterized by multiple chromosomal rearrangements. Moreover, sarcomas very frequently maintain their telomeres by recombination in the process called Alternative Lengthening of Telomeres (ALT) which enables their continuous growth and immortalization. Previously our group showed that orphan receptors bind specifically to the ALT telomeres and that their presence is important for the ALT mechanism. In these studies we focus on the function of orphan receptors at the telomeres and their contribution to telomeric recombination. We demonstrate that orphan receptors induce proximity of their binding sites in telomeric and genomic context and reveal novel aspects of ALT which are telomere-genome rearrangements which can underlie complexity of sarcomas. Our data perturb the dogma of telomere function in protecting the genome integrity. Here we show that in some cases telomeres may in fact drive genomic instability and chromosomal rearrangements by recombination with genomic sites. Characterization of TRF2 and orphan receptor NR2F/C2 binding sites in ALT (-) and ALT (+) cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Jérôme Déjardin

PROVIDER: E-GEOD-46237 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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NR2C/F orphan receptors induce telomere-genome rearrangements in ALT

Project description:Most sarcomas have complex karyotype and are characterized by multiple chromosomal rearrangements. Moreover, sarcomas very frequently maintain their telomeres by recombination in the process called Alternative Lengthening of Telomeres (ALT) which enables their continuous growth and immortalization. Previously our group showed that orphan receptors bind specifically to the ALT telomeres and that their presence is important for the ALT mechanism. In these studies we focus on the function of orphan receptors at the telomeres and their contribution to telomeric recombination. We demonstrate that orphan receptors induce proximity of their binding sites in telomeric and genomic context and reveal novel aspects of ALT which are telomere-genome rearrangements which can underlie complexity of sarcomas. Our data perturb the dogma of telomere function in protecting the genome integrity. Here we show that in some cases telomeres may in fact drive genomic instability and chromosomal rearrangements by recombination with genomic sites.

2015-02-23 | GSE46237 | GEO

Homo sapiens

Project description:NR2C/F orphan receptors induce telomere-genome rearrangements in ALT

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The role of SMCHD1 in the formation of constitutive heterochromatin

Project description:A large portion of the mammalian genome is assembled into constitutive heterochromatin which is highly compact and transcriptionally silent throughout the cell cycle. On the molecular level it is characterized by DNA methylation, “repressive” histone marks (hypoacethylation, H3K9 trimethylation, H4K20 trimethylation) and the presence of heterochromatin protein 1 (HP1). Regions of constitutive heterochromatin such as telomeres, pericentromeres and centromeres play a critical role in the maintenance of the genome integrity. Using a technique called Proteomics of Isolated Chromatin Segments (PICh) we have identified SMCHD1 as a novel component of telomeres and pericentomeres. SMCHD1 was previously shown to be involved in the inactivaction of the X chromosome and imprinting, but the its exact role in these processes is not understood. Our study aims to unravel the role of SMCHD1 in the formation and/or maintenance of constitutive chromatin. Using human cancer cells as research model we are trying to discover its mechanism of action by identifying its interacting partners, characterizing its genome wide binding sites and characterizing the effect of SMCHD1 knockout on the heterochromatin function. Characterization of SMCHD1 binding sites in HCT-116 cells.

2015-05-01 | E-GEOD-46462 | biostudies-arrayexpress

TERRA interactome in human ALT cancer cells identified by iDRiP-MS method

Project description:Alternative Lengthening of Telomeres (ALT) cancer cells are a subset of cancers that depend on the homologous recombination mechanism to extend their telomere length independent of telomerase. ALT cells contain elevated levels of the telomeric-repeat containing long noncoding RNA (TERRA), which is an RNA transcribed by RNA polymerase II and can form RNA:DNA (R-loops) hybrids at telomeres. Lines of evidence have shown that the formation of R-loops at telomeres could be one of the mechanisms to trigger DNA repair to lengthen telomeres. We perform iDRiP-MS, a method to capture specific RNA interacting protein by UV light crosslinking using antisense probe capture (Chu et al., 2017a; Minajigi et al., 2015), to explore the TERRA interactomes in human ALT cancer cell. Our TERRA interactome data reveals that TERRA interacts with an extensive subset of DNA repair proteins in ALT cells including the endonuclease XPF, suggesting that TERRA R-loops activate DDR via XPF to promote homologous recombination and telomere replication to drive ALT.

2022-09-28 | PXD028882 | Pride

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

DAXX Suppression of ALT

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>

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Telomeres reforged with non-telomeric sequences in mouse embryonic stem cells (Iso-seq)

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

Telomeres reforged with non-telomeric sequences in mouse embryonic stem cells (WGS)

2020-12-30 | GSE147914 | GEO