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The human TTAGGG Repeat Factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats

ABSTRACT: The study of the proteins that bind to telomeric DNA in mammals has provided a deep understanding of the mechanisms of chromosome-end protection. However, very little is known on the binding of these proteins to nontelomeric DNA sequences. The TTAGGG DNA repeat proteins 1 and 2 (TRF1 and TRF2) bind to mammalian telomeres as part of the shelterin complex and are essential for maintaining chromosome end stability. In this study, we combined chromatin immunoprecipitation with high-throughput sequencing to map at high sensitivity and resolution, the human chromosomal sites to which TRF1 and TRF2 bind. While most of the identified sequences correspond to telomeric regions, we showed that these two proteins also bind to extratelomeric sites. The vast majority of these extra-telomeric sites contains interstitial telomeric sequences (or ITSs). However we also identified non-ITS sites, which are also satellite DNA but the ones mainly constitutive of centromeric and pericentromeric regions. Interestingly, the TRF-binding sites are often located in the proximity of genes or within introns. We propose that, by binding to extratelomeric sequences, TRF1 and TRF2 couple the functional state of telomeres to the long-range organization of chromosomes and gene regulation networks.

ORGANISM(S): Homo sapiens

PROVIDER: GSE26005 | GEO | 2011/05/04

SECONDARY ACCESSION(S): PRJNA135515

REPOSITORIES: GEO

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The human TTAGGG Repeat Factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats

Project description:The study of the proteins that bind to telomeric DNA in mammals has provided a deep understanding of the mechanisms of chromosome-end protection. However, very little is known on the binding of these proteins to nontelomeric DNA sequences. The TTAGGG DNA repeat proteins 1 and 2 (TRF1 and TRF2) bind to mammalian telomeres as part of the shelterin complex and are essential for maintaining chromosome end stability. In this study, we combined chromatin immunoprecipitation with high-throughput sequencing to map at high sensitivity and resolution, the human chromosomal sites to which TRF1 and TRF2 bind. While most of the identified sequences correspond to telomeric regions, we showed that these two proteins also bind to extratelomeric sites. The vast majority of these extra-telomeric sites contains interstitial telomeric sequences (or ITSs). However we also identified non-ITS sites, which are also satellite DNA but the ones mainly constitutive of centromeric and pericentromeric regions. Interestingly, the TRF-binding sites are often located in the proximity of genes or within introns. We propose that, by binding to extratelomeric sequences, TRF1 and TRF2 couple the functional state of telomeres to the long-range organization of chromosomes and gene regulation networks. ChIP-SEQ experiment of transformed human fibroblast BJ cells with 3 antibodies (1 monoclonal anti-TRF1, 1 monoclonal anti-TRF2, 1 polyclonal anti-TRF2) and a negative control (proteinG without antibody used as the ChIP background)

2011-05-03 | E-GEOD-26005 | biostudies-arrayexpress

ZNF524 directly binds telomeres and supports their integrity via TRF2/RAP1

Project description:Telomeres are nucleoprotein structures at the ends of linear chromosomes. In humans, they consist of TTAGGG repeats, which are bound by dedicated proteins such as the shelterin complex. This complex consists of six proteins (TRF1, TRF2, RAP1, POT1, TPP1 and TIN2) and blocks unwanted DNA damage repair at telomeres, e.g. by suppressing non-homologous end joining (NHEJ) through its subunit TRF2. While shelterin does not work autonomously, additional direct telomere binding proteins have been described to function in a supplementary role. We here describe ZNF524, a zinc finger protein that directly binds to telomeric repeats with nanomolar affinity and reveal the base-specific sequence recognition by co-crystallization with telomeric DNA. ZNF524 localizes to telomeres and specifically maintains the presence of the TRF2/RAP1 subcomplex at telomeres without affecting the other shelterin members. Loss of ZNF524 concomitantly results in an increase in DNA damage signaling and recombination events. Overall, we identified ZNF524 as a direct telomere binding protein and propose that ZNF524 is involved in the maintenance of telomere integrity by promoting TRF2/RAP1 subcomplex binding.

2023-10-22 | PXD031416 | Pride

ZNF524 directly binds telomeres and supports their integrity via TRF2/RAP1

2023-10-21 | PXD024630 | Pride

Telomere Binding Protein TRB1 Preferentially Associates with Promoters of Translation Machinery genes

Project description:Background: Recently we characterised TRB1, a protein from a single-myb-histone family, as a structural and functional component of telomeres in Arabidopsis thaliana. TRB proteins, besides their ability to bind specifically telomeric DNA using their N-terminally positioned myb-like domain of the same type as in human TRF1 or TRF2 shelterin proteins, possess also histone-like domain which is involved in protein-protein interactions e.g., with POT1b. We set to investigate the genome-wide localization pattern of TRB1 to reveal its preferential mode of binding to chromatin in vivo and its potential functional roles in the genome-wide context. Results: Our results demonstrate that in addition to its roles at telomeres, TRB1 is preferentially associated with promoter regions of genes involved in ribosome biogenesis. This preference coincides with a frequent occurrence of telobox motifs in the upstream regions of genes in this category, but is not restricted to the telobox presence. Conclusions: We conclude that TRB1, in addition to its preferential telomeric localization, shows a specific genome-wide distribution pattern suggesting its role in regulation of genes involved in biogenesis of translational machinery. TRB1 DNA-binding activity investigated in 2 biological replicates (2 immunoprecipitation approaches) with controls; with technical replicates.

2015-12-21 | E-GEOD-69431 | biostudies-arrayexpress

Phosphorylation of TRF2 promotes its interaction with TIN2 and regulates DNA repair at damaged telomeres

Project description:Protein phosphatase magnesium-dependent 1 delta (PPM1D) is involved in termination of the cell cycle checkpoint by counteracting activity of the tumour suppressor protein p53. By dephosphorylating various proteins at chromatin, PPM1D contributes to the control of DNA damage response and DNA repair. Using proximity biotinylation followed by proteomic analysis, we identified interaction between PPM1D and the components of the shelterin complex that protects telomeric DNA. Interaction between PPM1D and TRF2 was confirmed by immunoprecipitation and proximity ligation assay. Confocal microscopy revealed colocalisation of the endogenous PPM1D with TRF2 at telomeres. Further, we found that TRF2 was phosphorylated by ATR at S410 after induction of DNA damage at telomeres and this modification was increased in cells lacking PPM1D or after PPM1D inhibition. Phosphorylation of TRF2 stimulated its interaction with TIN2 at telomeres and in vitro. Conversely, overexpression of PPM1D impaired localisation of TIN2 at telomeres. Finally, inhibition of PPM1D impaired recruitment of 53BP1 and RAD51 to DNA double strand breaks at telomeres. Expression of TRF2-S410A mutant fully rescued the recruitment of 53BP1 to telomeric breaks. These results suggest that TRF2 phosphorylation promotes association of TIN2 with the shelterin complex and regulates DNA repair at telomeres.

2023-03-11 | PXD035268 | Pride

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. Characterization of TRF2 and orphan receptor NR2F/C2 binding sites in ALT (-) and ALT (+) cells.

2015-02-23 | E-GEOD-46237 | biostudies-arrayexpress

Ubiquitin C-terminal hydrolase isozyme L1 (UCHL1) is associated with shelterin complex at interstitial telomeric sites

Project description:Ubiquitin C-terminal hydrolase isozyme L1 (UCHL1) is primarily expressed in neuronal cells and neuroendocrine cells. It is a multifunctional protein involved in deubiquitination, ubiquitination, and ubiquitin homeostasis. UCHL1 has been associated with various diseases, including many cancers, but its specific roles are disputed and still generally undetermined. Herein, we demonstrate that UCHL1 is associated with genomic DNA in certain prostate cancer cell lines, including DU 145 cells derived from a brain metastatic site, and in HEK293T embryonic kidney cells with a neuronal lineage. Chromatin immunoprecipitation and sequencing revealed that UCHL1 localizes to TTAGGG repeats at telomeres and interstitial telomeric sequences, as do TRF1 and TRF2, components of the shelterin complex. A weak or transient interaction between UCHL1 and the shelterin complex was confirmed by immunoprecipitation and proximity ligation assays. UCHL1 and TERF2IP, also a component of the shelterin complex, were bound to the nuclear scaffold. UCHL1 may play a role in regulating gene expression by affecting the stabilization of the shelterin proteins or influencing nuclear targeting. As several shelterin proteins (TRF1, TRF2, POT1 and TERF2IP) are ubiquitinated, UCHL1 may have a role in regulating the stability of these proteins. UCHL1 may also regulate the nuclear location of shelterin-associated genomic regions.

2018-02-23 | GSE97111 | GEO

Telomere Binding Protein TRB1 Preferentially Associates with Promoters of Translation Machinery genes

2015-12-21 | GSE69431 | GEO

Phosphorylation of TRF2 promotes its interaction with TIN2 and regulates DNA repair at damaged telomeres.

Project description:Protein phosphatase magnesium-dependent 1 delta (PPM1D) terminates the cell cycle checkpoint by dephosphorylating the tumour suppressor protein p53. By targeting additional substrates at chromatin, PPM1D contributes to the control of DNA damage response and DNA repair. Using proximity biotinylation followed by proteomic analysis, we identified a novel interaction between PPM1D and the shelterin complex that protects telomeric DNA. In addition, confocal microscopy revealed that endogenous PPM1D colocalized with TRF2 at telomeres. Further, we found that ATR phosphorylated TRF2 at S410 after induction of DNA double strand breaks at telomeres and this modification increased after inhibition or loss of PPM1D. TRF2 phosphorylation stimulated its interaction with TIN2 both in vitro and at telomeres. Conversely, induced expression of PPM1D impaired localisation of TIN2 and TPP1 at telomeres. Finally, recruitment of the DNA repair factor 53BP1 to the telomeric breaks was strongly reduced after inhibition of PPM1D and was rescued by the expression of TRF2-S410A mutant. Our results suggest that TRF2 phosphorylation promotes the association of TIN2 within the shelterin complex and regulates DNA repair at telomeres.

2023-03-11 | PXD035273 | Pride

TERRA RNA antagonizes ATRX and protects telomeres

Project description:Through an integration of genomic and proteomic approaches to advance understanding of long noncoding RNAs, we investigate the function of the telomeric transcript, TERRA. By identifying thousands of TERRA target sites in the mouse genome, we demonstrate that TERRA can bind both in cis to telomeres and in trans to genic targets. We then define a large network of interacting proteins, including epigenetic factors, telomeric proteins, and the RNA helicase, ATRX. TERRA and ATRX share hundreds of target genes and are functionally antagonistic at these loci: whereas TERRA activates, ATRX represses gene expression. At telomeres, TERRA competes with telomeric DNA for ATRX binding, suppresses ATRX localization, and ensures telomeric stability. Depleting TERRA increases telomerase activity and induces telomeric pathologies, including formation of telomere-induced DNA damage foci and loss or duplication of telomeric sequences. We conclude that TERRA functions as an epigenomic modulator in trans and as an essential regulator of telomeres in cis.

2017-06-29 | GSE79180 | GEO

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