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Genome-wide binding of wild-type p53 and R248Q missense mutant variants in isogenic human acute myeloid leukemia (AML) cell lines

ABSTRACT: Genome-wide binding of wild-type p53 and R248Q missense mutant variants in isogenic human acute myeloid leukemia (AML) cell lines

PROVIDER: PRJNA1198371 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31719233_1.fastq.gz	Fastqsanger.gz
	SRR31719233_2.fastq.gz	Fastqsanger.gz
	SRR31719234_1.fastq.gz	Fastqsanger.gz
	SRR31719234_2.fastq.gz	Fastqsanger.gz
	SRR31719235_1.fastq.gz	Fastqsanger.gz

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Genome-wide binding of wild-type p53 and R248Q missense mutant variants in isogenic human acute myeloid leukemia (AML) cell lines

Project description:TP53, encoding for the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, have remained enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We generated isogenic human leukemia cell lines of the most common TP53 missense mutations using CRISPR/Cas9. Functional, DNA binding, and transcriptional analyses revealed loss-of-function (LOF) without GOF effects of missense mutations. Comprehensive mutational scanning of p53 single amino acid variants demonstrated that DNA-binding domain missense variants exert dominant-negative effects (DNE). The precise functional and molecular mechanisms of the DNE have remained elusive. Using a variety of novel model systems including CRISPR-edited human isogenic cell lines, transcriptional reporter cell lines, and targeted protein degradation assays combined with functional and molecular analyses we functionally characterize the DNE and demonstrate that formation of heterotetramers between R248Q and WT p53 impairs proper WT p53 functionality by preventing DNA binding and subsequent target gene transactivation.

2025-03-14 | GSE284299 | GEO

Transcriptional consequences of wild-type and missense mutant p53 in isogenic human acute myeloid leukemia (AML) cell lines

Project description:TP53, encoding for the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, have remained enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We generated isogenic human leukemia cell lines of the most common TP53 missense mutations using CRISPR/Cas9. Functional, DNA binding, and transcriptional analyses revealed loss-of-function (LOF) without GOF effects of missense mutations. Comprehensive mutational scanning of p53 single amino acid variants demonstrated that DNA-binding domain missense variants exert dominant-negative effects (DNE). In mice, DNE of p53 missense variants confer a selective advantage on hematopoietic cells upon DNA damage in vivo. Clinical outcomes in acute myeloid leukemia patients showed no evidence of GOF for TP53 missense mutations. These findings establish dominant-negativity as the primary unit of selection for TP53 missense mutations in myeloid malignancies.

2019-08-30 | GSE131592 | GEO

Genome-wide binding of wild-type and missense mutant p53 in isogenic human acute myeloid leukemia (AML) cell lines

Project description:TP53, encoding for the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, have remained enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We generated isogenic human leukemia cell lines of the most common TP53 missense mutations using CRISPR/Cas9. Functional, DNA binding, and transcriptional analyses revealed loss-of-function (LOF) without GOF effects of missense mutations. Comprehensive mutational scanning of p53 single amino acid variants demonstrated that DNA-binding domain missense variants exert dominant-negative effects (DNE). In mice, DNE of p53 missense variants confer a selective advantage on hematopoietic cells upon DNA damage in vivo. Clinical outcomes in acute myeloid leukemia patients showed no evidence of GOF for TP53 missense mutations. These findings establish dominant-negativity as the primary unit of selection for TP53 missense mutations in myeloid malignancies.

2019-08-30 | GSE131484 | GEO

Transcriptional consequences of wild-type and missense mutant p53 in isogenic human acute myeloid leukemia (AML) cell lines

Project description:Transcriptional consequences of wild-type and missense mutant p53 in isogenic human acute myeloid leukemia (AML) cell lines

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Genome-wide binding of wild-type and missense mutant p53 in isogenic human acute myeloid leukemia (AML) cell lines

Project description:Genome-wide binding of wild-type and missense mutant p53 in isogenic human acute myeloid leukemia (AML) cell lines

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NFKB1 Missense Variants

Project description:1 Novel Missense Variants in Patients with Primary Immunodeficiency and Immune dysregulation

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Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer.

Project description:Mutant p53 proteins, resulting from the missense mutations of the TP53 tumor suppressor gene, possess gain-of-function activities and are among the most robust oncoproteins in human tumors. They are potentially important therapeutic targets. No studies to date have distinguished common, therapeutically relevant mutant p53 gain-of-function effects from effects specific to different mutant variants and cell backgrounds. here we performed RNA-seq analysisin MDA-MB-231 (R280K) upon silencing TP53 or the control siRNA.

2016-04-27 | GSE68248 | GEO

Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer.

Project description:Mutant p53 proteins, resulting from the missense mutations of the TP53 tumor suppressor gene, possess gain-of-function activities and are among the most robust oncoproteins in human tumors. They are potentially important therapeutic targets. No studies to date have distinguished common, therapeutically relevant mutant p53 gain-of-function effects from effects specific to different mutant variants and cell backgrounds. here we perform the analysis of transcriptomes,rRegardless of the cell background, of different mutant p53s.

2016-04-27 | GSE65458 | GEO

Rare germline heterozygous missense variants of the BRCA1-Associated Protein 1 gene, BAP1, heterozygous missense variants cause a syndromic neurodevelopmental disorder

Project description:Nuclear deubiquitinase BAP1 (BRCA1-Associated Protein 1) is a core component of multiprotein complexes that promote transcription by reversing the ubiquitination of histone 2A (H2A). BAP1 is a tumor suppressor gene whose germline loss-of-function variants predispose to cancer. To our knowledge, there are very rare examples of different germline variants in the same gene causing either a NDD or a tumor predisposition syndrome. Here, we report a series of 11 de novo germline heterozygous missense BAP1 variants associated with a rare syndromic neurodevelopmental disorder (NDD). Functional analysis showed that most of the variants cannot rescue the consequences of BAP1 inactivation, suggesting a loss-of-function mechanism. In T cells isolated from two affected children, H2A deubiquitination was impaired in matching peripheral blood mononuclear cells, histone H3 K27 acetylation ChIP-seq indicated that these BAP1 variants induced genome-wide chromatin state alterations, with enrichment for regulatory regions surrounding genes of the ubiquitin-proteasome system (UPS). Altogether, these results define a clinical syndrome caused by rare germline missense BAP1 variants that alter chromatin remodeling through abnormal histone ubiquitination and lead to transcriptional dysregulation of developmental genes.

2021-12-10 | GSE190394 | GEO

Systematic phenotypic characterization and integrated analysis show heterogeneous neomorphic activities of different missense mutant p53 proteins

Project description:The phenotypic and transcriptomic data on ten normal breast epithelial cell lines each expressing a distinct missense mutant p53 protein, and their systems-level analysis through ChIP-Seq and RNA-seq defines the molecular basis for phenotypic heterogeneity imparted by the different missense mutant p53 proteins. The focus of the study is to gain mechanistic insight on the neomorphic function of mutant p53 proteins and their manifestation into phenotypic heterogeneity in the context of a TNBC model.

2023-09-21 | GSE162341 | GEO

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