Unveiling the biological effects of DNA G-quadruplex ligands through multi-omics data integration
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1209075 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31958006.fastq.gz | Fastqsanger.gz | |||
| SRR31958007.fastq.gz | Fastqsanger.gz | |||
| SRR31958008.fastq.gz | Fastqsanger.gz | |||
| SRR31958009.fastq.gz | Fastqsanger.gz | |||
| SRR31958010.fastq.gz | Fastqsanger.gz |
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Project description:G-quadruplexes (G4s) are non-canonical DNA structures that have proved to play a pivotal role in various biological processes, including telomere maintenance and gene expression regulation. Owing to their prevalence in tumor cells, G4s have emerged as promising targets for cancer therapy, with a substantial body of research demonstrating the potential of G4 ligands as anti-cancer tools. However, a more comprehensive understanding of G4 binders’ mode of action is imperative to successfully translate them into therapeutic agents. Herein, we employed a multi-omics approach, integrating transcriptomics, proteomics and metabolomics, to identify key signaling pathways that mediate the anti-cancer effects of well-characterized G4-binding agents (berberine, PDS and RHPS4) on HeLa cancer cells. Our results revealed that, under the investigated experimental conditions, berberine treatment only had negligible cellular effects, whereas PDS-treated HeLa cells underwent significant changes at the transcriptomic, proteomic and metabolomic levels, with marked impairment in glycolysis, antioxidant capacity, lipids and nucleotides biosynthetic processes. Notably, RHPS4 could selectively affect mitochondrial activity, possibly through the specific stabilization of mitochondrial G-quadruplex structures. Overall, our findings provide a valuable multi-omics perspective on the cellular changes driven by G-quadruplex binders, that may accelerate the development of G4-targeted therapies.
2025-05-20 | GSE286401 | GEO
Project description:The G-quadruplex is an alternative DNA structural motif that is considered to be functionally important in the mammalian genome. Herein, we address the hypothesis that G-quadruplex structures can exist within double-stranded genomic DNA using a G-quadruplex-specific probe. An engineered antibody is employed to enrich for DNA containing G-quadruplex structures, followed by deep sequencing to detect and map G-quadruplexes at high resolution in genomic DNA from human breast adenocarcinoma cells. Our high sensitivity structure-based pull-down strategy enables the isolation of genomic DNA fragments bearing a single as well as multiple G-quadruplex structures. Stable G-quadruplex structures are found in sub-telomeres, gene bodies and gene regulatory regions. For a sample of identified target genes, we show that G-quadruplex stabilizing ligands can modulate transcription. These results confirm the existence of G-quadruplex structures and their persistence in human genomic DNA. Four independent libraries have been enriched in DNA G-quadruplex structures using a G-quadruplex-specific probe. One genomic input library was sequenced as control. Deep-sequencing of these libraries allowed the mapping of G-quadruplexes on the genome.
2013-05-08 | E-GEOD-45241 | biostudies-arrayexpress
Project description:The G-quadruplex is an alternative DNA structural motif that is considered to be functionally important in the mammalian genome. Herein, we address the hypothesis that G-quadruplex structures can exist within double-stranded genomic DNA using a G-quadruplex-specific probe. An engineered antibody is employed to enrich for DNA containing G-quadruplex structures, followed by deep sequencing to detect and map G-quadruplexes at high resolution in genomic DNA from human breast adenocarcinoma cells. Our high sensitivity structure-based pull-down strategy enables the isolation of genomic DNA fragments bearing a single as well as multiple G-quadruplex structures. Stable G-quadruplex structures are found in sub-telomeres, gene bodies and gene regulatory regions. For a sample of identified target genes, we show that G-quadruplex stabilizing ligands can modulate transcription. These results confirm the existence of G-quadruplex structures and their persistence in human genomic DNA.
2013-05-08 | GSE45241 | GEO
Project description:A375 and HT1080 cells are treated with G-quadruplex ligands PDS or PhenDC3 following genome-wide shRNA knockdown. This enables the identification of genes that when silenced, specifically compromises cell growth in the presence of the ligand. First, a pilot screen was performed to determine a ligand concentration and experimental duration that caused ligand-specific, significant changes in shRNA levels. Second, a genome-wide screen was performed to globally evaluate G4-ligand synthetic lethal interactions. Third, to corroborate the G4-sensitisers uncovered in the genome-wide screen, a focussed screen was performed with a custom shRNA pool.
2019-06-22 | E-MTAB-6367 | biostudies-arrayexpress
Project description:In this study we discover proteins that bind to G4 quadruplex DNA structure. We use modified c-myc quadruplex as a bait, and compare it to the control bait - T15 oligo. We use spectral counts and G-test to determine significant binders. T15 and G4 datafiles are uploaded
2016-07-07 | PXD003501 | Pride
Project description:DNA damage and genome instability by G-quadruplex ligands are mediated by R-loops in human cancer cells
| PRJNA476585 | ENA
Project description:ARID1A, a subunit of the BAF chromatin remodeler, is frequently mutated in cancer. Predicting how ARID1A loss impacts cancer therapy response is challenging because it influences many cellular pathways. G quadruplex (G4) binding ligands, such as pyridostatin, show anticancer effects, but the genetic determinants influencing the response to G4 ligands are not fully understood. Here, we show that ARID1A-deficient cells are selectively sensitive to pyridostatin compared to isogenic controls. This was apparent in ovarian and colorectal cancer cell line models, and in vivo studies suggest that G4 ligands hold promise for ARID1A-deficient cancers. While ARID1A modulates pyridostatin-induced transcriptional responses, we show that toxicity in ARID1A-deficient cells arises from the defective repair of topoisomerase-induced breaks. Notably, these cells fail to efficiently accumulate non-homologous end joining proteins on chromatin following pyridostatin exposure. These data uncover a role for ARID1A in the cellular response to G4 ligands, linking remodeling to G4 ligand-induced responses.
2025-08-13 | GSE295547 | GEO
Project description:G-quadruplexes (G4s) and R-loops are non-canonical DNA structures that can play regulatory functions of basic nuclear processes and can trigger DNA damage and genome instability. We here show that specific G4 ligands can stabilize G4s and simultaneously increase R-loop levels in human cancer cells likely by spreading DNA:RNA heteroduplexes to adjacent regions containing G4 structures. DNA cleavage and DNA damage response induced by G4 ligands were rescued by overexpression of exogenous RNaseH1 in cancer cells independently of BRCA2 status. The data thus show that R-loops are involved in the induction of DNA damage by chemical G4 stabilization. In addition, G4 ligands trigger the formation of micronuclei, particularly in BRCA2-silenced cancer cells, in an R-loop dependent manner. Our results uncover the mechanism of genome instability caused by G4 ligands and can open to the development of unexpected anticancer strategies using G4-targeted agents.
2018-12-27 | GSE115957 | GEO
Project description:The effect of bisquinolinium compounds PhenDC3 and 360A genome wide gene expression changes modulated via promoter based G-quadruplex (G4) motifs. The total RNA was extracted after treating HeLa S3 cells with 10 µM of no molecule (DMSO), 8979A (control molecule), PhenDC3 (G4 specific molecule) or 360A (G4 specific molecule) for 48 hrs in triplicate.
2012-05-29 | E-GEOD-32170 | biostudies-arrayexpress
Project description:ARID1A is a subunit of the BAF chromatin remodelling complex that is frequently mutated in cancer. However, it is challenging to predict how ARID1A loss might impact on responses to cancer therapies because it participates in many different cellular pathways. G quadruplex (G4) binding ligands, such as pyridostatin, have shown anticancer effects, but the pathways and genetic determinants involved in the response to G4 ligands are still not fully understood. Here, we show that ARID1A deficient cells are selectively sensitive to G4 binding ligands when compared with isogenic controls. Sensitivity to G4 ligands was apparent in both ovarian clear cell and colorectal cancer cell line models, and in vivo studies suggest that G4 ligands might hold promise for treating ARID1A deficient cancers. While we find that ARID1A loss impacts on the transcriptional response to pyridostatin, we find that the influence of ARID1A on pyridostatin-mediated toxicity is driven by the DNA repair response to topoisomerase activity. Specifically, we find that ARID1A deficient cells are unable to efficiently accumulate nonhomologous end joining proteins onto chromatin following exposure to pyridostatin, providing mechanistic insights into their impaired survival. These data uncover a role for ARID1A in the cellular response to G4 ligands, and link chromatin remodelling to G4 ligand-induced DNA damage responses and genome instability.
2025-08-15 | PXD063556 | Pride