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Oxidized 5-methylcytosine modulates synthetic lethality to poly-ADP-ribose polymerase inhibitors in acute myeloid leukemia

ABSTRACT: Oxidized 5-methylcytosine modulates synthetic lethality to poly-ADP-ribose polymerase inhibitors in acute myeloid leukemia

PROVIDER: PRJNA899655 | ENA |

REPOSITORIES: ENA

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			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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Oxidized 5-methylcytosine modulates synthetic lethality to poly-ADP-ribose polymerase inhibitors in acute myeloid leukemia [cell line RNA-seq]

Project description:Oxidized 5-methylcytosine modulates synthetic lethality to poly-ADP-ribose polymerase inhibitors in acute myeloid leukemia [cell line RNA-seq]

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Oxidized 5-methylcytosine modulates synthetic lethality to poly-ADP-ribose polymerase inhibitors in acute myeloid leukemia [murine AE9a RNA-seq]

Project description:Oxidized 5-methylcytosine modulates synthetic lethality to poly-ADP-ribose polymerase inhibitors in acute myeloid leukemia [murine AE9a RNA-seq]

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Oxidized 5-methylcytosine modulates synthetic lethality to poly-ADP-ribose polymerase inhibitors in acute myeloid leukemia [murine AE9a RNA-seq]

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.

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Oxidized 5-methylcytosine modulates synthetic lethality to poly-ADP-ribose polymerase inhibitors in acute myeloid leukemia [cell line RNA-seq]

2022-11-12 | GSE217585 | GEO

Oxidized 5-methylcytosine modulates synthetic lethality to poly-ADP-ribose polymerase inhibitors in acute myeloid leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-11-12 | GSE217587 | GEO

ADP-ribose derived Nuclear ATP is Required for Chromatin Remodeling and Hormonal Gene Regulation

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

Erasure of Tet-oxidized 5-methylcytosine by a SRAP nuclease

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.

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Deletion of TIPARP increases sensitivity to dioxin-induced hepatosteatosis and lethality

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

Engineering Af1521 macro domain increases ADP-ribose binding affinity and leads to the identification of more ADP-ribosylated proteins

Project description:Protein ADP-ribosylation is a covalent, reversible post-translational modification that has important functions in several cellular mechanisms. The identification of modified proteins in cells has proven challenging and, due to the low abundance of protein ADP-ribosylation, has mainly been possible via enrichment methodologies using ADP-ribose binding domains. Here, using random mutagenesis and in vitro selection with an ADP-ribosylated histone peptide, we engineered the archaeal Af1521 macro domain to generate an engineered isoform containing nine mutations that displays significantly increased affinity towards ADP-ribose. Comparison of the wild-type and the engineered Af1521 macro domains using our proteomic ADP-ribosylome enrichment workflow demonstrated an increased identification rate of ADP-ribosylated proteins with the engineered Af1521.

2020-10-20 | PXD016686 | Pride

Comprehensive ADP-ribosylome analysis identifies tyrosine as an ADP-ribose acceptor site

Project description:Despite recent mass spectrometry (MS)-based breakthroughs, comprehensive ADP-ribose (ADPr)-site identification and localization remain challenging. Here, we report the establishment of an unbiased, multistep ADP-ribosylome data analysis workflow that led to the identification of tyrosine as a novel ARTD1/PARP1 dependent in vivo ADPr-acceptor. MS analyses of in vitro ADP-ribosylated proteins confirmed tyrosine as an ADPr-acceptor amino acid in RPS3A (Y155) and HPF1 (Y238) and demonstrated that trans modification of RPS3A is dependent on HPF1. We provide an ADPr-site Localization Spectra Database (ADPr-LSD), which contains 288 high-quality ADPr-modified peptide spectra, to serve as ADPr spectral references for correct ADPr-site localizations.

2018-06-28 | PXD009948 | Pride

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