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Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita

ABSTRACT: Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita

PROVIDER: PRJNA559864 | ENA |

REPOSITORIES: ENA

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Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita (microarray)

Project description:Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita (microarray)

| PRJNA559866 | ENA

Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita (HITS-CLIP)

Project description:Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita (HITS-CLIP)

| PRJNA559865 | ENA

Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita (microarray)

Project description:We identify nucleophosmin (NPM1) as an essential regulator of 2’-O-methylation on rRNA by directly binding C/D box small nucleolar RNAs (snoRNAs), thereby modulating translation. We demonstrate the importance of 2’-O-Me regulated translation for cellular growth, differentiation and hematopoietic stem cells (HSC) maintenance, and show that Npm1-inactivation in adult HSCs results in bone marrow failure (BMF). We identify NPM1 germline mutations in DC patients presenting with BMF; and demonstrate that they are deficient in snoRNA binding. CRISPR knock-in mice harboring the DC germline NPM1 mutation recapitulate both hematological and non-hematological features of DC. Thus, our findings provide a direct demonstration of the role of 2’-O-Me in the pathogenesis of human disease

2019-08-13 | GSE135725 | GEO

Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita (HITS-CLIP)

2019-08-13 | GSE135724 | GEO

Germline NPM1 mutations lead to altered rRNA 2'-O-methylation and cause dyskeratosis congenita.

Project description:RNA modifications are emerging as key determinants of gene expression. However, compelling genetic demonstrations of their relevance to human disease are lacking. Here, we link ribosomal RNA 2'-O-methylation (2'-O-Me) to the etiology of dyskeratosis congenita. We identify nucleophosmin (NPM1) as an essential regulator of 2'-O-Me on rRNA by directly binding C/D box small nucleolar RNAs, thereby modulating translation. We demonstrate the importance of 2'-O-Me-regulated translation for cellular growth, differentiation and hematopoietic stem cell maintenance, and show that Npm1 inactivation in adult hematopoietic stem cells results in bone marrow failure. We identify NPM1 germline mutations in patients with dyskeratosis congenita presenting with bone marrow failure and demonstrate that they are deficient in small nucleolar RNA binding. Mice harboring a dyskeratosis congenita germline Npm1 mutation recapitulate both hematological and nonhematological features of dyskeratosis congenita. Thus, our findings indicate that impaired 2'-O-Me can be etiological to human disease.

| S-EPMC6858547 | biostudies-literature

Germline NPM1 mutations lead to altered rRNA 2’-O-methylation and cause dyskeratosis congenita

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

2019-08-13 | GSE135726 | GEO

NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation

Project description:Nucleophosmin (NPM1) is a nucleolar protein and one of the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the commonly detected frameshift mutations in exon12 (NPM1c), previous studies have identified NPM1 gene rearrangements leading to the expression of NPM1-fusion proteins in pediatric AML. However, whether the NPM1-fusions are indeed oncogenic and how the NPM1-fusions cause AML have been largely unknown. In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1-MLF1 and NPM1-CCDC28A. NPM1-MLF1 is present in both the nucleus and cytoplasm and occasionally induces AML in the mouse transplantation assay (2/12). NPM1-CCDC28A localizes predominantly to the cytoplasm, immortalizes mouse bone marrow cells in vitro and efficiently (5/6) induces AML in vivo. Mechanistically, both NPM1-fusions bind to the HOX gene cluster and, like NPM1c, cause aberrant upregulation of HOX genes in cooperation with XPO1. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions. Thus, our study provides experimental evidence that both NPM1-MLF1 and NPM1-CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 may be a promising strategy for the NPM1-rearranged AML.

2024-08-14 | GSE274558 | GEO

NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation [Cut & Run]

2024-08-14 | GSE274559 | GEO

miRNA-seq of microRNAs from control or PARN depleted HeLa cells

Project description:PARN deficiency is linked to the inherited disease Dyskeratosis Congenita and Familial Pulmonary Fibrosis. The aim of this experiment is to identify miRNAs that are regulated by PARN in human cells, deficiency of which could explain the disease phenotype in patients.

2018-12-29 | E-MTAB-7547 | biostudies-arrayexpress

Comparison of ribosomes between control and dyskerin-depleted human cells

Project description:Dyskerin is a pseudouridine synthase involved in fundamental cellular processes (including rRNA and snRNA modification and telomere stabilization), whose function is altered in X-linked dyskeratosis congenita and cancer. Dyskerin role in ribosome processing was suggested to underlie the alterations in mRNA translation described in cells lacking dyskerin function. We compared the protein contents of 5 replicates of ribosomal preparations from control or dyskerin-depleted human cells.

2015-05-07 | PXD001274 | Pride

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