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G-quadruplex stabilizer CX-5461 effectively combines with ionizing radiation to selectively target ATRX-deficient malignant glioma [CUT&Tag]

ABSTRACT: Mutational inactivation of ?-thalassaemia/mental retardation X-linked (ATRX) represents a defining molecular feature in large subsets of adult and pediatric malignant glioma. ATRX deficiency gives rise to abnormal G-quadruplex (G4) DNA secondary structures at GC-rich regions of the genome, altering chromatin accessibility and enhancing DNA damage. Building on earlier work, we sought to assess the extent to which pharmacological G4 stabilization selectively enhances DNA damage and cell death in preclinical models of ATRX-deficient glioma. To investigate the effect of G4 stabilization on histone variant H3.3 deposition on the genome, we treated patient-derived glioma stem cells (GSCs) with G4 stabilizer CX-5461 and performed cleavage under targets and tagmentation (CUT&Tag) for H3.3. Our analyses show that G4 stabilizer CX-541 disrupts H3.3 deposition in ATRX-deficient GSCs and likely enhances replication stress and DNA damage.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261562 | GEO | 2024/03/18

REPOSITORIES: GEO

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G-quadruplex stabilizer CX-5461 effectively combines with ionizing radiation to selectively target ATRX-deficient malignant glioma [RNA-seq]

Project description:Mutational inactivation of α-thalassaemia/mental retardation X-linked (ATRX) represents a defining molecular feature in large subsets of adult and pediatric malignant glioma. ATRX deficiency gives rise to abnormal G-quadruplex (G4) DNA secondary structures at GC-rich regions of the genome, altering chromatin accessibility and enhancing DNA damage. Building on earlier work, we sought to assess the extent to which pharmacological G4 stabilization selectively enhances DNA damage and cell death in preclinical models of ATRX-deficient glioma. Deploying the G4 stabilizer CX-5461 in patient-derived glioma stem cells (GSCs) in vitro and in GSC murine flank and intracranial xenografts in vivo, we evaluated efficacy as both a single agent and in combination with ionizing radiation (IR), a central element of current treatment standards. CX-5461 promoted dose-sensitive lethality in ATRX-deficient GSCs relative to ATRX-intact controls. Mechanistic studies revealed that CX-5461 disrupted histone variant H3.3 deposition, enhanced replication stress and DNA damage pathways, activated p53-independent apoptosis, and induced G2/M arrest selectively in ATRX-deficient GSCs. These data were corroborated in vivo, where we notably demonstrated that combinational treatment leads to profound tumor growth delay and prolonged survival exclusively in ATRX-deficient flank tumors. In its totality, our work substantively demonstrates efficacy and defines mechanisms of action for a novel therapeutic strategy targeting ATRX-deficient malignant glioma, laying the groundwork for clinical translation.

2024-03-18 | GSE261563 | GEO

RAD51 ChIP-seq post treatment with CX-5461

Project description:We discovered two small molecule drugs - CX-5461 and CX-3543 - with specific toxicity against BRCA deficiencies in cancer cells and xenograft models. Both CX-5461 and CX-3543 have been previously recognized as RNA pol I inhibitors. CX-5461 is in advanced phase 1 trials for treatment of lymphoma and leukemia through rDNA transcription inhibition in a p53-dependent mechanism. We have discovered a novel activity of CX-5461, as a stabilizer of G-quadruplex DNA sequences inside cells the same as CX-3543. We found that BRCA1 and BRCA2 deficiency markedly increases (one log order) sensitivity to CX-5461 and a related drug CX-3543 in human cancer cell lines and polyclonal patient derived xenograft models, providing a direct therapeutic hypothesis, including PDX tumours resistant to PARP inhibition. We show that in epithelial cells, exposure to CX-5461 and CX-3543 blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543 induced DNA damage and failure to do so leads to lethality. RNA pol I inhibition is not a required component of the cell killing mechanism in these tumours, because BRCA2 deficient cells are not more sensitive to BMH-21, a more potent rDNA transcription inhibitor. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumors deficient for DNA damage repair. Since CX-5461 is already in advanced phase 1 trials for other indications, this has resulted in immediately testable translational implications (Canadian trial, NCT02719977, opened May 2016) as no phase-1 eligible G4 stabilizers have been described to date.

2016-12-06 | GSE90967 | GEO

TERRA regulates DNA G-quadruplex formation and ATRX loading on chromatin

Project description:The genome consists of non-B-DNA structures such as G-quadruplexes (G4) that are involved in the regulation of genome stability and transcription. Telomeric-repeat containing RNA (TERRA) is capable of folding into G-quadruplex and interacting with chromatin remodeler ATRX. Here we show that TERRA modulates ATRX occupancy on repetitive sequences and over genes, and maintains DNA G-quadruplex structures at TERRA target and non-target sites in mouse embryonic stem cells. TERRA prevents ATRX from binding to subtelomeric regions and represses H3K9me3 formation. G4 ChIP-seq reveals that G4 abundance decreases at accessible chromatin regions, particularly at transcription start sites (TSS) after TERRA depletion; such G4 reduction at TSS is associated with elevated ATRX occupancy and differentially expressed genes. Loss of ATRX alleviates the effect of gene repression caused by TERRA depletion. Immunostaining analyses demonstrate that knockdown of TERRA diminishes DNA G4 signals, whereas silencing ATRX elevates G4 formation. Our results uncover an epigenetic regulation by TERRA that sequesters ATRX and preserves DNA G4 structures.

2022-11-09 | GSE194038 | GEO

Histone H3G34R mutation causes replicative stress, defective homologous recombination and genomic instability in Fission Yeast

Project description:Recurrent somatic mutations of H3F3A in aggressive pediatric high-grade gliomas generate K27M or G34R mutant histone H3.3. H3.3-G34R mutants are common in tumors additionally mutant for p53 and ATRX, an H3.3-specific chromatin remodeler. To gain insight into the role of H3-G34R, we generated fission yeast that express only the mutant histone H3. H3-G34R specifically reduces H3K36 tri-methylation and H3K36 acetylation, but minimally affects transcriptional control. H3-G34R mutants exhibit genomic instability and increased replicative stress including slowed replication fork restart although DNA replication checkpoints are functional. H3-G34R mutants are defective for DNA damage repair by homologous recombination (HR), and on damage have altered HR protein dynamics suggestive that H3-G34R slows resolution of HR-mediated repair. In summary our analysis of H3-G34R mutant fission yeast provides mechanistic insight into how G34R mutation may promote genomic instability in glioma.

2017-07-20 | GSE96842 | GEO

Histone H3-G34V and H3-G34R mutant fission yeast exhibit distinct chromatin changes and different DNA damage sensitivities.

2018-11-15 | GSE106979 | GEO

DNA damage and genome instability by G-quadruplex ligands are mediated by R-loops in human cancer cells

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

Effects of the G-quadruplex-binding drugs Quarfloxin and CX-5461 on the malaria parasite Plasmodium falciparum

Project description:P. falciparum is the deadliest causative agent of human malaria. This parasite has historically developed resistance to many drugs, including the current frontline treatments, so new therapeutic targets are needed Our previous work on guanine quadruplexes (G4s) in the parasite’s DNA and RNA has highlighted their influence on parasite biology, and also revealed G4 stabilising compounds as promising candidates for drug repositioning. In particular, quarfloxin, a former anticancer agent, kills blood-stage parasites at all developmental stages, with fast rates of kill and nanomolar potency. Here we explored the molecular mechanism of quarfloxin and its related derivative CX-5461. In vitro, both compounds bound to P. falciparum-encoded G4 sequences. In cellulo, quarfloxin was more potent than CX-5461, and could prevent establishment of blood-stage malaria in vivo in a murine model. CX-5461 showed clear DNA damaging activity, as reported in human cells, while quarfloxin caused weaker signatures of DNA damage. Both compounds caused transcriptional dysregulation in the parasite, but the affected genes were largely different, again suggesting different modes of action. Therefore, CX-5461 may act primarily as a DNA damaging agent in both Plasmodium parasites and mammalian cells, whereas the complete anti-malarial mode of action of quarfloxin may be parasite-specific, and remains elusive.

2024-01-02 | GSE235142 | GEO

G-quadruplex stabilizer CX-5461 effectively combines with ionizing radiation to selectively target ATRX-deficient malignant glioma [CUT&Tag]

Project description:G-quadruplex stabilizer CX-5461 effectively combines with ionizing radiation to selectively target ATRX-deficient malignant glioma [CUT&Tag]

| PRJNA1087451 | ENA

G-quadruplex stabilizer CX-5461 effectively combines with ionizing radiation to selectively target ATRX-deficient malignant glioma [RNA-seq]

Project description:G-quadruplex stabilizer CX-5461 effectively combines with ionizing radiation to selectively target ATRX-deficient malignant glioma [RNA-seq]

| PRJNA1087450 | ENA

HLTF Prevents G4 Accumulation and Promotes G4-induced Fork Slowing to Maintain Genome Stability

Project description:G-quadruplexes (G4s) form throughout the genome and influence important cellular processes, but their deregulation can challenge DNA replication fork progression and threaten genome stability. Here, we demonstrate an unexpected, dual role for the dsDNA translocase HLTF in G4 metabolism. First, we find that HLTF is enriched at G4s in the human genome and suppresses G4 accumulation throughout the cell cycle using its ATPase activity. This function of HLTF affects telomere maintenance by restricting alternative lengthening of telomeres, a process stimulated by G4s. We also show that HLTF and MSH2, a mismatch repair factor that binds G4s, act in independent pathways to suppress G4s and to promote resistance to G4 stabilization. In a second, distinct role, HLTF restrains DNA synthesis upon G4 stabilization by suppressing PrimPol-dependent repriming. Together, the dual functions of HLTF in the G4 response prevent DNA damage and potentially mutagenic replication to safeguard genome stability.

2024-08-13 | GSE247967 | GEO

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