Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Loss of full-length hnRNP R isoform impairs DNA damage response in motoneurons by inhibiting Yb1 recruitment to chromatin

ABSTRACT: Neurons critically rely on the functions of RNA-binding proteins to maintain their polarity and resistance to neurotoxic stresses. HnRNP R has a diverse range of post-transcriptional regulatory functions and is important for neuronal development by regulating axon growth. Hnrnpr pre-mRNA undergoes alternative splicing to produce transcripts encoding two isoforms: a full-length protein and a shorter form lacking the N-terminal acidic domain. While the neuronal defects produced by total hnRNP R depletion have been investigated before, the individual functions of each hnRNP R isoforms are unknown. We generated a Hnrnpr knockout mouse (Hnrnprtm1a/tm1a) showing selective loss of the full-length hnRNP R isoform. Motoneurons cultured from Hnrnprtm1a/tm1a mice did not show any axonal growth defects. However, they show an accumulation of double-strand breaks and an impaired DNA damage response. Proteomic analysis of the hnRNP R interactome revealed the multifunctional protein Yb1 as a top interactor. Yb1 depleted motoneurons also exhibit defects in DNA damage repair. We show that Yb1 is recruited to chromatin upon DNA damage, a mechanism that is dependent on full-length hnRNP R. Our findings thus suggest a novel role of hnRNP R in maintaining genomic integrity and highlight the function of its Nterminal acidic domain in this context.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Mario Oroshi

LAB HEAD: Matthias Mann

PROVIDER: PXD026407 | Pride | 2021-11-01

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Similar Datasets

Loss of full-length hnRNP R isoform impairs DNA damage response in motoneurons by inhibiting Yb1 recruitment to Chromatin

Project description:Neurons critically rely on the functions of RNA-binding proteins to maintain their polarity and resistance to neurotoxic stresses. HnRNP R has a diverse range of post-transcriptional regulatory functions and is important for neuronal development by regulating axon growth. Hnrnpr pre-mRNA undergoes alternative splicing to produce transcripts encoding two protein isoforms: a full-length protein and a shorter form lacking the N-terminal acidic domain. While the neuronal defects produced by total hnRNP R depletion have been investigated before, the individual functions of each hnRNP R isoforms are unknown. We generated a Hnrnpr knockout mouse (Hnrnprtm1a/tm1a) showing selective loss of the full-length hnRNP R isoform. Motoneurons cultured from Hnrnprtm1a/tm1a mice did not show any axonal growth defects. However, they show an accumulation of double-strand breaks and an impaired DNA damage response. Proteomic analysis of the hnRNP R interactome revealed the multifunctional Y-box binding protein 1 (Yb1) as a top interactor. Yb1 depleted motoneurons also exhibit defects in DNA ´damage repair. We show that Yb1 is recruited to chromatin upon DNA damage, a mechanism that is dependent on full length hnRNP R. Our findings thus suggest a novel role of hnRNP R in maintaining genomic integrity and highlight the function of its N-terminal acidic domain in this context.

2021-11-01 | PXD022467 | Pride

hnRNP R and its main interactor, the noncoding RNA 7SK, coregulate the axonal transcriptome of motoneurons

Project description:Disturbed RNA processing and subcellular transport contribute to the pathomechanisms of motoneuron diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. RNA-binding proteins are involved in these processes, but the mechanisms how they regulate the subcellular diversity of transcriptomes, in particular in axons, are not understood. hnRNP R interacts with several proteins involved in motoneuron diseases. It is located in axons of developing motoneurons and its depletion causes defects in axon growth. Here, we used iCLIP to determine the RNA interactome of hnRNP R in motoneurons. We identified ~3,500 RNA targets, predominantly with functions in synaptic transmission and axon guidance. Among the RNA targets identified by iCLIP, the non-coding RNA 7SK was the top interactor of hnRNP R. We detected 7SK in the nucleus but also in the cytosol of motoneurons. In axons, 7SK localized in close proximity to hnRNP R and depletion of hnRNP R reduced axonal 7SK. Furthermore, suppression of 7SK led to defective axon growth that was accompanied by axonal transcriptome alterations similar to those caused by hnRNP R depletion. Using a series of 7SK deletion mutants we show that the function of 7SK in axon elongation depends on its interaction with hnRNP R but not with the pTEF-B complex involved in transcriptional regulation. These results propose a role of 7SK as essential interactor of hnRNP R to regulate its function in axon maintenance.

2018-03-06 | GSE77101 | GEO

Ptbp2 modulates axon growth in motoneurons through axonal localization and translation of Hnrnpr

Project description:The neuronal RNA-binding protein Ptbp2 regulates neuronal differentiation by modulating alternative splicing programs in the nucleus. Such programs contribute to axonogenesis by adjusting the levels of protein isoforms involved in axon growth and branching. While its functions in alternative splicing have been described in detail, cytosolic roles of Ptbp2 for axon growth have remained elusive. Here, we show that Ptbp2 is located in the cytosol and in axons of motoneurons, and that depletion of Ptbp2 affects axon growth. We identified Ptbp2 as a major interactor of the 3' UTR of Hnrnpr mRNA. Axonal localization of Hnrnpr mRNA and local synthesis of hnRNP R protein are strongly reduced when Ptbp2 is depleted, leading to defective axon growth. Ptbp2 regulates hnRNP R translation by mediating the association of Hnrnpr with ribosomes in a manner dependent on the translation factor eIF5A2. Our data thus, suggest a mechanism whereby Ptbp2 modulates axon growth by fine-tuning the mRNA transport and local synthesis of an RNA-binding protein.

2023-07-13 | PXD035196 | Pride

The novel role of hnRNP UL1 in rDNA transcription and rDNA repair in human cell nucleoli

Project description:hnRNP UL1 plays an important function in cell nuclei, where it is recruited to DNA damage sites and is involved in the repair of DNA double strand breaks. Furthermore, this protein is known as a transcriptional repressor of RNA polymerase II genes. In the present study, we have shown that hnRNP UL1 is also localized in the nucleoli. Revealing its function, we figured out that hnRNP UL1 stimulates rDNA gene transcription and may be involved in the transport of the proteins between the nucleolus and the nucleoplasm. Moreover, we observed that cells with hnRNP UL1 silencing are more sensitive to DNA damage, suggesting its role in rDNA repair pathways and nucleolar genome integrity. Indeed, we confirmed that hnRNP UL1 interacts with yH2A.X, RPA32, XRCC1, and Chk1 in cell nucleoli, suggesting its involvement in repairing of DNA damages.

2022-10-15 | PXD033233 | Pride

isoCirc catalogs full-length circular RNA isoforms in human transcriptomes

Project description:We report isoCirc, a long-read sequencing strategy coupled with an integrated computational pipeline to characterize full-length circular RNA (circRNA isoforms) using rolling circle amplification (RCA) followed by long-read sequencing. Applying isoCirc to 12 human tissues, we determined full-length structures and examined tissue specificities of circRNA isoforms in human transcriptomes.

2020-09-12 | GSE141693 | GEO

Gene expression profile analysis of HepG2 cells upon PSTAR or hnRNP K knockdown

Project description:We discovered lncRNA PSTAR as a novel hepatocellular carcinoma (HCC) - associated lncRNA, which could interact with hnRNP K protein. To explore the function of PSTAR in HCC and underlying molecular mechanism, we examined the global gene expression change in HepG2 cells with PSTAR knockdown. The gene expression profile of HepG2 with hnRNP K knockdown was also analyzed to investigate the correlationship between PSTAR and hnRNP K. Further, doxorubicin (DOX) was applied to induce DNA damage, and the effect of PSTAR and hnRNP K under DNA damage was also investigated.

2016-05-26 | GSE81878 | GEO

Global transcriptome profiling of SETD2 and hnRNP L depleted cells and H3K36me3 profile of WT 293T cells

Project description:We performed RNA-seq of 293T cells post depletion and SETD2 or hnRNP L to compare their global transcriptome profile. We also looked at the distribution of the histone mark H3K36me3 in wild type 293T to correlate it with the observed transcriptome changes upon SETD2 and hnRNP L depletion. We rescued SETD2 knock out 293T cells with SETD2 FL (Full Length), FLΔSRI (FLwoSRI) and FLΔSHI (FLwoSHI) and performed H3K36me3 ChIP-Seq.

2021-01-29 | GSE151296 | GEO

isoCirc catalogs full-length circular RNA isoforms in human transcriptomes

Project description:isoCirc catalogs full-length circular RNA isoforms in human transcriptomes

| PRJNA594380 | ENA

Aberrant splicing isoforms detected by full-length transcriptome sequencing as transcripts of potential neoantigens in non-small cell lung cancer

Project description:To identify aberrant splicing isoforms and potential neoantigens, we performed full-length cDNA sequencing of lung adenocarcinoma cell lines using a long-read sequencer MinION. We constructed a comprehensive catalog of aberrant splicing isoforms and detected isoform-specific peptides using proteome analysis.

2020-12-09 | PXD019915 | JPOST Repository

C. elegans - starvation and UV

Project description:DNA damage comprises a causal factor for aging and aging-associated diseases. Defects in genome maintenance pathways give rise to a variety of human congenital syndromes that are characterized by growth retardation, cancer susceptibility, and accelerated aging. The specific consequences of unrepaired DNA damage in human diseases are particularly apparent in syndromes caused by distinct nucleotide excision repair (NER) defects, however, with yet poorly understood genotype-phenotype correlations and highly complex disease phenotypes. We have established that the equivalent mutations in the simple metazoan Caenorhabditis elegans reflect the distinct outcomes of DNA repair defects and allow investigating the consequences of persistent DNA damage during animal development and aging. Here, we employed proteome, lipidome, and phosphoproteome analysis of NER-deficient animals in response to UV treatment in order to gain comprehensive insights into the full range of physiological adaptations to the presence of unrepaired DNA damage. We derive metabolic changes indicative of a tissue maintenance program and implicate an autophagy-mediated protoestatic response. We assign central roles for the IIS regulator DAF-2 and the EGF-signalling pathway in orchestrating this adaptive response to DNA damage. Our results provide new insights into the DNA damage responses in the organismal context.

2017-08-22 | PXD005649 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data