Oxidized 5-methylcytosine modulates synthetic lethality to poly-ADP-ribose polymerase inhibitors in acute myeloid leukemia
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ABSTRACT:
PROVIDER: PRJNA899655 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22240600_1.fastq.gz | Fastqsanger.gz | |||
| SRR22240600_2.fastq.gz | Fastqsanger.gz | |||
| SRR22240601_1.fastq.gz | Fastqsanger.gz | |||
| SRR22240601_2.fastq.gz | Fastqsanger.gz | |||
| SRR22240602_1.fastq.gz | Fastqsanger.gz |
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Project description:Oxidized 5-methylcytosine modulates synthetic lethality to poly-ADP-ribose polymerase inhibitors in acute myeloid leukemia [murine AE9a RNA-seq]
| PRJNA899657 | ENA
Project description:Oxidized 5-methylcytosine modulates synthetic lethality to poly-ADP-ribose polymerase inhibitors in acute myeloid leukemia [cell line RNA-seq]
| PRJNA899656 | ENA
Project description:TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with AML. Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via BER that slows leukemia progression. We utilized genetic and compound library screening approaches to identify rational combination treatment strategies to improve the use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several FDA approved drugs, vitamin C treatment with PARPi elicited a strong synergistic effect at blocking AML self-renewal in murine and human AML models. Vitamin C-mediated TET activation combined with PARPi caused an enrichment of chromatin-bound PARP1 at oxidized mCs, and H2AX accumulation during mid-S phase leading to cell-cycle stalling and differentiation. Given most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant.
2022-11-12 | GSE217586 | GEO
Project description:TET2 haploinsufficiency is a driving event in myeloid cancers and is associated with a worse prognosis in patients with AML. Enhancing residual TET2 activity using vitamin C increases oxidized 5-methylcytosine (mC) formation and promotes active DNA demethylation via BER that slows leukemia progression. We utilized genetic and compound library screening approaches to identify rational combination treatment strategies to improve the use of vitamin C as an adjuvant therapy for AML. In addition to increasing the efficacy of several FDA approved drugs, vitamin C treatment with PARPi elicited a strong synergistic effect at blocking AML self-renewal in murine and human AML models. Vitamin C-mediated TET activation combined with PARPi caused an enrichment of chromatin-bound PARP1 at oxidized mCs, and H2AX accumulation during mid-S phase leading to cell-cycle stalling and differentiation. Given most AML subtypes maintain residual TET2 expression, vitamin C could elicit broad efficacy as a PARPi therapeutic adjuvant.
2022-11-12 | GSE217585 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-11-12 | GSE217587 | GEO
Project description:Enzymatic oxidation of 5-methylcytosine (5mC) in DNA by the Tet (Ten-eleven translocation) family of dioxygenases reprograms genome function during pre-implantation development and in primordial germ cells. Tet-oxidized derivatives of 5mC such as 5-hydroxymethylcytosine (5hmC) act as transient intermediates in DNA demethylation or serve as stable epigenetic marks, yet how these alternate fates are specified at individual CpGs is not understood. Here, we report that the Sos-response associated peptidase (SRAP) domain-containing protein Srap1, the mammalian orthologue of an ancient protein superfamily operonically associated with the DNA damage response in bacteria and bacteriophage, binds directly and selectively to Tet-oxidized forms of 5mC in DNA and catalyses turnover of these bases to unmodified cytosine by an autopeptidase cleavage-coupled endonuclease. Biallelic inactivation of Srap1 in mouse embryonic stem (ES) cells results in the global accumulation of Tet-oxidized 5mC derivatives, with ectopic 5hmC in promoters of highly expressed genes, across gene bodies and within enhancer elements. Srap1 deficiency causes partially penetrant lethality in late blastocysts prior to uterine implantation, while surviving midgestation embryos exhibit aberrant patterns of DNA methylation associated with altered gene expression, including hypermethylation in regions closely linked to ectopic 5hmC detected earlier in development. Thus, highly specific removal of 5hmC and its oxidized derivatives by Srap1 sustains genome-wide DNA methylation homeostasis. These findings establish a function for a previously unknown structural class of DNA base modification-specific eraser enzymes that combine the catalytic properties of an autopeptidase with endonuclease activation, and position Srap1 as a key determinant of 5mC demethylation trajectories during mammalian embryonic development.
2017-10-10 | GSE81222 | GEO
Project description:Key nuclear processes in eukaryotes including DNA replication or repair and gene regulation require extensive chromatin remodeling catalyzed by energy consuming enzymes. How the energetic demands of such processes are ensured in response to rapid stimuli remains unclear. We have analyzed this question in the context of the massive gene regulation changes induced by progestins in breast cancer cells and found that ATP is generated in the cell nucleus via the hydrolysis of poly-ADP-ribose to ADP-ribose. Nuclear ATP synthesis requires the combined enzymatic activities of PARP1, PARG and NUDIX5/NUDT5. Although initiated via mitochondrial derived ATP, the nuclear source of ATP is essential for hormone induced chromatin remodeling, gene regulation and cell proliferation and may also participate in DNA repair. This novel pathway reveals exciting avenues of research for drug development.
2017-12-23 | GSE64467 | GEO
Project description:Background: Uterine leiomyosarcoma (uLMS) has a poor prognosis owing to its resistance to chemotherapy. Therefore, novel therapeutic targets for uLMS should be identified. Suppressor license of variegation 3-9 homolog 2 (SUV39H2) is a histone methyltransferase that promotes the repair of double-stranded DNA breaks by recruiting phosphorylated H2AX (γH2AX). In this study, we investigated the potential therapeutic targets of SUV39H2 in uLMS and the mechanism of synthetic lethality between PARP inhibitors and the SUV39H2 inhibitor OTS186935. Methods: First, we analyzed the mRNA and protein expression of SUV39H2 in the clinical tissues of uLMS, normal myometrium, and leiomyomas using real-time polymerase chain reaction and immunohistochemistry, respectively. Next, we conducted drug sensitivity assays for OTS186935 alone and in combination with olaparib, a poly (ADP-ribose) polymerase inhibitor, using the uLMS cell lines SK-LMS-1 and SK-UT-1. We performed Western blotting, immunofluorescence, and chromatin immunoprecipitation sequencing (ChIP-seq) to investigate γH2AX following OTS186935 treatment in addition to in vivo experiments using nude mice with subcutaneously implanted uLMS. Results: SUV39H2 expression in uLMS was significantly higher than that in the normal myometrium and leiomyomas. OTS186935 decreased the viability of both cell lines, and its combination with olaparib resulted in synthetic lethality in SK-UT-1 cells (combination index = 0.88). After treatment with OTS186935, γH2AX accumulation decreased. ChIP-seq also showed downregulation of γH2AX following OTS186935 treatment. Notably, the combination of OTS186935 and a PARP inhibitor was significantly more effective in vivo. Conclusion: OTS186935 inhibited double-stranded DNA break repair, as evidenced by γH2AX downregulation by ChIP-seq and other assays. OTS186935 combined with olaparib induces synthetic lethality in patients with uLMS.
2025-05-28 | GSE297686 | GEO
Project description:Background: Uterine leiomyosarcoma (uLMS) has a poor prognosis owing to its resistance to chemotherapy. Therefore, novel therapeutic targets for uLMS should be identified. Suppressor license of variegation 3-9 homolog 2 (SUV39H2) is a histone methyltransferase that promotes the repair of double-stranded DNA breaks by recruiting phosphorylated H2AX (γH2AX). In this study, we investigated the potential therapeutic targets of SUV39H2 in uLMS and the mechanism of synthetic lethality between PARP inhibitors and the SUV39H2 inhibitor OTS186935. Methods: First, we analyzed the mRNA and protein expression of SUV39H2 in the clinical tissues of uLMS, normal myometrium, and leiomyomas using real-time polymerase chain reaction and immunohistochemistry, respectively. Next, we conducted drug sensitivity assays for OTS186935 alone and in combination with olaparib, a poly (ADP-ribose) polymerase inhibitor, using the uLMS cell lines SK-LMS-1 and SK-UT-1. We performed Western blotting, immunofluorescence, and chromatin immunoprecipitation sequencing (ChIP-seq) to investigate γH2AX following OTS186935 treatment in addition to in vivo experiments using nude mice with subcutaneously implanted uLMS. Results: SUV39H2 expression in uLMS was significantly higher than that in the normal myometrium and leiomyomas. OTS186935 decreased the viability of both cell lines, and its combination with olaparib resulted in synthetic lethality in SK-UT-1 cells (combination index = 0.88). After treatment with OTS186935, γH2AX accumulation decreased. ChIP-seq also showed downregulation of γH2AX following OTS186935 treatment. Notably, the combination of OTS186935 and a PARP inhibitor was significantly more effective in vivo. Conclusion: OTS186935 inhibited double-stranded DNA break repair, as evidenced by γH2AX downregulation by ChIP-seq and other assays. OTS186935 combined with olaparib induces synthetic lethality in patients with uLMS.
2025-05-28 | GSE297689 | GEO
Project description:The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that mediates the toxic effects of the environmental contaminant, dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD). Dioxin causes a diverse range of toxic responses, including hepatic damage and lethal wasting syndrome; however, the mechanisms of dioxin-induced toxicity are still unknown. Here we show that the loss of TCDD-inducible poly(ADP-ribose) polymerase (TIPARP; ARTD14), an ADP-ribosyltransferase and AHR repressor, increases sensitivity to dioxin-induced toxicity and lethality. Tiparp-/- mice treated with a single injection of 100 mg/kg dioxin display an accelerated lethal wasting syndrome with no Tiparp-/- mice surviving beyond day 5; all Tiparp+/+ mice survived up to 30 days post treatment. Tiparp-/- mice displayed dramatic increases in liver steatosis and hepatotoxicity. At the molecular level, TIPARP selectively ADP-ribosylates AHR, but not AHR nuclear translocator (ARNT) and the Tiparp-dependent repression of AHR is reversed by the ADP-ribosylase and macrodomain containing protein MacroD1, but not MacroD2. These results describe previously unidentified roles for Tiparp, MacroD1, and ADP-ribosylation in AHR signaling, dioxin toxicity and lethality. 12 samples were analyzed. There were 4 treatment groups and each treatment group was done in triplicate. Gene expression changes were determine in hepatic RNA isolated from (1) corn oil treated C57BL/6;129Sv mice; (2) 30 ug/kg/bw 2,3,7,8-Tetrachlorodibenzo-p-dioxin C57BL/6;129Sv mice; (3) corn oil treated C57BL/6;129Sv Tiparp-/- mice; and (4) 30 ug/kg/bw 2,3,7,8-Tetrachlorodibenzo-p-dioxin C57BL/6;129Sv Tiparp-/- mice
2015-05-14 | E-GEOD-61534 | biostudies-arrayexpress