Telomerase function and binding at endogenous G-rich regions (ChIP)
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ABSTRACT:
PROVIDER: PRJNA599159 | ENA |
REPOSITORIES: ENA
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Project description:Telomerase function and binding at endogenous G-rich regions
| PRJNA599158 | ENA
Project description:Telomerase majorly functions at telomeres but under adverse conditions acts at endogenous regions, which is often observed in cancer calls. By mapping the global occupancy of the catalytic subunit of telomerase (Est2), we reveal that telomerase binds to multiple genomic loci, which we termed ‘non-telomere-binding sites’ (NTBS). We characterized under when and why Est2 binds to such sites and could show that telomerase is inactive but becomes activated upon global DNA damage. Indicating that those regions are of particular risk for genome stability. Using biochemical and molecular experiments we further characterized Est2 binding to NTBS. In contrast to Est2 binding to telomere neither Cdc13 nor Ku70/80 is crucial for the binding to NTBS. Strikingly, using Hi-C, we demonstrate that chromatin organization is essential and drives the interaction of Est2-NTBS binding. The here presented results provide a novel model of telomerase regulation using endogenous regions as “parking spots” awaiting its canonical function at telomeres.
2020-01-07 | GSE143184 | GEO
Project description:Telomerase majorly functions at telomeres but under adverse conditions acts at endogenous regions, which is often observed in cancer calls. By mapping the global occupancy of the catalytic subunit of telomerase (Est2), we reveal that telomerase binds to multiple genomic loci, which we termed ‘non-telomere-binding sites’ (NTBS). We characterized under when and why Est2 binds to such sites and could show that telomerase is inactive but becomes activated upon global DNA damage. Indicating that those regions are of particular risk for genome stability. Using biochemical and molecular experiments we further characterized Est2 binding to NTBS. In contrast to Est2 binding to telomere neither Cdc13 nor Ku70/80 is crucial for the binding to NTBS. Strikingly, using Hi-C, we demonstrate that chromatin organization is essential and drives the interaction of Est2-NTBS binding. The here presented results provide a novel model of telomerase regulation using endogenous regions as “parking spots” awaiting its canonical function at telomeres.
2020-01-07 | GSE143186 | GEO
Project description:Telomerase function and binding at endogenous G-rich regions (Hi-C Seq)
| PRJNA599165 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-01-07 | GSE143187 | GEO
Project description:Gene repression and silencers are poorly understood. We reasoned that H3K27me3-rich regions (MRRs) of the genome defined from clusters of H3K27me3 peaks may be used to identify silencers that can regulate gene expression via proximity or looping. MRRs were associated with chromatin interactions and interact preferentially with each other. MRR component removal at interaction anchors by CRISPR led to upregulation of interacting target genes, altered H3K27me3 and H3K27ac levels at interacting regions, and altered chromatin interactions. Chromatin interactions did not change at regions with high H3K27me3, but regions with low H3K27me3 and high H3K27ac levels showed changes in chromatin interactions. The MRR knockout cells also showed changes in phenotype associated with cell identity, and altered xenograft tumor growth. MRR-associated genes and long-range chromatin interactions were susceptible to H3K27me3 depletion. Our results characterized H3K27me3-rich regions and their mechanisms of functioning via looping.
2020-12-01 | GSE133183 | GEO
Project description:We have identified two previously uncharacterized proteins involved in telomerase biogenesis. Both proteins are required for telomerase activity and telomere length maintenance. We named these proteins Thc1 (Telomerase Holoenzyme Component 1) and Bmc1 (Bin3/MePCE 1) based on structural and sequence similarities to the nuclear cap binding complex and the methyl phosphate capping enzyme (Bin3/MePCE) in metazoans, respectively. Thc1 and Bmc1 function together with Pof8 in recognizing telomerase RNA and promoting the recruitment of the Lsm2-8 complex and the catalytic subunit to assemble functional telomerase.
2021-05-22 | GSE174822 | GEO
Project description:Ribonucleoprotein enzymes require specific and dynamic conformations of their RNA constituents for regulated catalysis. Telomerase RNA components (TRs) rely on two conserved domains, a pseudoknot/template sequence and a three-way junction (CR4/5), each of which binds the telomerase reverse transcriptase protein (TERT). Vertebrate TRs evolved a third element, the H/ACA domain, involved in assembly and trafficking of telomerase through binding telomerase cofactors, dyskerin and TCAB1, respectively. Here, we show that telomerase unexpectedly requires TCAB1 for enzyme catalysis and for shaping the conformation of the TR CR4/5 domain. Human and mouse cells lacking TCAB1 exhibit a marked reduction in telomerase activity, but show no defect in enzyme assembly. Instead, loss of TCAB1 causes specific unfolding of critical RNA helices in TR CR4/5 required for catalysis, and impairs TR-TERT association. CR4/5 mutations derived from patients with the telomere disorder dyskeratosis congenita phenocopy the loss of enzyme activity and disruption of TERT binding observed with TCAB1 deletion. These findings show that the H/ACA element acquired by telomerase during vertebrate evolution serves an unanticipated role in controlling folding of the essential TR CR4/5 domain, facilitating optimal TERT engagement and enabling telomerase catalysis through the action of TCAB1 protein tethered at the H/ACA domain.
2018-06-24 | GSE97486 | GEO
Project description:H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions
| PRJNA550207 | ENA
Project description:Telomerase deficiency and progressive telomere erosion in human somatic cells results in senescence. Small RNAs that target telomeres have been observed in diverse organisms but their functions are not well characterized. We define an endogenous small RNA pathway in Caenorhabditis elegans that promotes heterochromatin formation at telomeres via Dicer, the perinuclear Argonaute protein WAGO-1 and the nuclear Argonaute protein HRDE-1. Loss of telomerase induces biogenesis of siRNAs that target the telomeric lncRNA TERRA, whereas loss of both telomerase and small RNA-mediated telomeric silencing induces TERRA expression, DNA damage, and an accelerated sterility phenotype. The latter phenotypes can be rescued by exogenous telomeric siRNAs or by loss of the DNA damage response protein EXO-1. Thus, endogenous siRNAs interact with TERRA to promote heterochromatin formation in a manner that is critical for the stability of naturally eroding telomeres. We propose that small RNA-mediated heterochromatin defects could contribute to proliferative aging by promoting genome stability.
2019-03-13 | GSE111800 | GEO