Quadruplex ligand Tetra-Pt(bpy) Induces the Death of Human ALT Cancer Cells by Inhibiting Homologue Recombination-Mediated Telomere Elongation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE74029 | GEO | 2015/10/15
SECONDARY ACCESSION(S): PRJNA298773
REPOSITORIES: GEO
Similar Datasets
Project description:Pt-ttpy (tolyl terpyridin-Pt complex) covalently binds to G-quadruplex (G4) structures in vitro and to telomeres in cellulo via its Pt moiety. Here, we identified its targets in the human genome, in comparison to Pt-tpy, its derivative without G4 affinity, and cisplatin. Pt-ttpy, but not Pt-tpy, induces the release of the shelterin protein TRF2 from telomeres concomitantly to the formation of DNA damage foci at telomeres but also at other chromosomal locations. -H2AX chromatin immunoprecipitation (ChIP-seq) after treatment with Pt-ttpy or cisplatin revealed accumulation in G- and A-rich tandemly repeated sequences, but not particularly in potential G4 forming sequences. Collectively, Pt-ttpy presents dual targeting efficiency on DNA, by inducing telomere dysfunction and genomic DNA damage at specific loci.
2021-05-04 | GSE171450 | GEO
Project description:BackgroundRecent studies suggest that BRCA2 affects telomere maintenance. Interestingly, anti cancer treatments that involve BRCA2 and telomerase individually are currently being explored. In the light of the above recent studies their combinatorial targeting may be justified in the development of future treatments. In order to investigate effects of BRCA2 that can be explored for this combinatorial targeting we focused on the analysis of recombination rates at telomeres by monitoring T-SCEs (Telomere Sister Chromatid Exchanges).ResultsWe observed a significant increase in T-SCE frequencies in four BRCA2 defective human cell lines thus suggesting that BRCA2 suppresses recombination at telomeres. To test this hypothesis further we analyzed T-SCE frequencies in a set of Chinese hamster cell lines with or without functional BRCA2. Our results indicate that introduction of functional BRCA2 normalizes frequencies of T-SCEs thus supporting the notion that BRCA2 suppresses recombination at telomeres. Given that ALT (Alternative Lengthening of Telomeres) positive cells maintain telomeres by recombination we investigated the effect of BRCA2 depletion in these cells. Our results show that this depletion causes a dramatic reduction in T-SCE frequencies in ALT positive cells, but not in non-ALT cells.ConclusionBRCA2 suppresses recombination at telomeres in cells that maintain them by conventional mechanisms. Furthermore, BRCA2 depletion in ALT positive cells reduces high levels of T-SCEs normally found in these cells. Our results could be potentially important for refining telomerase-based anti-cancer therapies.
| S-EPMC3264516 | biostudies-literature
Project description:Chromatin immunoprecipitation of tetra-acetylated histone H4 followed by hybridization to genome-wide tiling microarrays demonstrated that tetra-acetylated H4 is enriched at the two chorion Drosophila amplicons in follicle cells (DAFC) as well as other non-amplified loci Comparison of tetra-acetylated H4 ChIP sample compared to input DNA for two different Drosophila strains
2011-05-27 | E-GEOD-29520 | biostudies-arrayexpress
Project description:Chromatin immunoprecipitation of tetra-acetylated histone H4 followed by hybridization to genome-wide tiling microarrays demonstrated that tetra-acetylated H4 is enriched at the two chorion Drosophila amplicons in follicle cells (DAFC) as well as other non-amplified loci
2011-05-27 | GSE29520 | GEO
Project description:One microbial organism always contains multiple DNA modification systems as defense strategies or epigenetic controls. Here, we describe crosstalk between two distinct DNA modifications with different target sequence motif: DNA phosphorothioation (PT, GPSAAC/GPSTTC by DndACDE proteins) and N6-methyl-adenine methylation (m6A, G6mATC by Dam protein). By using a newly developed DNA modification sequencing method PT nick-seq, we found that half of PT modifications change from GAAC/GTTC to GATC sites after bacteria have lost Dam.
2020-05-21 | GSE135910 | GEO
Project description:Promyelocytic leukemia (PML) bodies (also called ND10) are dynamic nuclear structures implicated in a wide variety of cellular processes. ALT-associated PML bodies (APBs) are specialized PML bodies found exclusively in telomerase-negative tumors in which telomeres are maintained by recombination-based alternative (ALT) mechanisms. Although it has been suggested that APBs are directly implicated in telomere metabolism of ALT cells, their precise role and structure have remained elusive. Here we show that PML bodies in ALT cells associate with chromosome ends forming small, spatially well-defined clusters, containing on average 2-5 telomeres. Using an innovative approach that gently enlarges PML bodies in living cells while retaining their overall organization, we show that this physical enlargement of APBs spatially resolves the single telomeres in the cluster, but does not perturb the potential of the APB to recruit chromosome extremities. We show that telomere clustering in PML bodies is cell-cycle regulated and that unique telomeres within a cluster associate with recombination proteins. Enlargement of APBs induced the accumulation of telomere-telomere recombination intermediates visible on metaphase spreads and connecting heterologous chromosomes. The strand composition of these recombination intermediates indicated that this recombination is constrained to a narrow time window in the cell cycle following replication. These data provide strong evidence that PML bodies are not only a marker for ALT cells but play a direct role in telomere recombination, both by bringing together chromosome ends and by promoting telomere-telomere interactions between heterologous chromosomes.
| S-EPMC2747187 | biostudies-literature
Project description:Alternative lengthening of telomeres (ALT) is a telomere-elongation mechanism observed in ∼15% of cancer subtypes. Current models indicate that ALT is mediated by homology-directed repair mechanisms. By disrupting MSH6 gene expression, we show that the deficiency of MutSα (MSH2/MSH6) DNA mismatch repair complex causes striking telomere hyperextension. Mechanistically, we show MutSα is specifically recruited to telomeres in ALT cells by associating with the proliferating-cell nuclear antigen (PCNA) subunit of the ALT telomere replisome. We also provide evidence that MutSα counteracts Bloom (BLM) helicase, which adopts a crucial role in stabilizing hyper-extended telomeres and maintaining the survival of MutSα-deficient ALT cancer cells. Lastly, we propose a model in which MutSα deficiency impairs heteroduplex rejection, leading to premature initiation of telomere DNA synthesis that coincides with an accumulation of telomere variant repeats (TVRs). These findings provide evidence that the MutSα DNA mismatch repair complex acts to restrain unwarranted ALT.
| S-EPMC8724847 | biostudies-literature
Project description:Tetra-Amelia with lung aplasia phenotype
| PRJNA438127 | ENA
Project description:PT ethanol extract and BO 24 h fermentation experiment.
2023-06-30 | MSV000092325 | MassIVE