Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Convergence of Cockayne Syndrome Group A and B Proteins at rRNA Transcription through Nucleolin Regulation

ABSTRACT: Cockayne Syndrome (CS) is a rare neurodegenerative disease characterized by short stature, cachexia, sun-sensitivity, accelerated aging, and short lifespan. Mutations in two human genes, ERCC8/CSA and ERCC6/CSB, are causative for CS and the protein products of these genes, CSA and CSB, while structurally unrelated, play roles in DNA repair and other aspects of DNA metabolism in human cells. Many clinical and molecular features of CS remain poorly understood, and it has been suggested that CSA and CSB regulate transcription of rDNA genes and ribosome biogenesis. The goal of this study was to investigate the dysregulation of rRNA synthesis in CS. Here, we report that Nucleolin (Ncl), a nucleolar protein that regulates rRNA synthesis and ribosome biogenesis, interacts specifically with CSA and CSB. In addition, CSA induces ubiquitination of Ncl, enhances binding of CSB to Ncl, and CSA and CSB both stimulate binding of Ncl to rDNA and subsequent rRNA synthesis. These findings suggest that CSA and CSB are positive regulators of rRNA synthesis via Ncl regulation. A majority of CS patients carry mutations in CSA and CSB and present with similar clinical features, thus our findings may provide novel insights into disease mechanism and the neuropathological features of CS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122736 | GEO | 2020/03/16

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Cockayne syndrome group A and ferrochelatase finely tune ribosomal gene transcription and its response to UV irradiation

Project description:CSA and CSB proteins are key players in transcription-coupled nucleotide excision repair (TC-NER) pathway that removes UV-induced DNA lesions from the transcribed strands of expressed genes. Additionally, CS proteins play relevant but still elusive roles in other cellular pathways whose alteration may explain neurodegeneration and progeroid features in Cockayne syndrome (CS). Here we identify a CSA-dependent chromatin-associated protein complex that modulates rRNA transcription. Besides RNA polymerase I (RNAP1) and specific ribosomal proteins (RPs), the CSA complex includes ferrochelatase (FECH), a well-known mitochondrial enzyme whose deficiency causes erythropoietic protoporphyria (EPP). Impairment of either CSA or FECH functionality leads to reduced RNAP1 occupancy on rDNA promoter that is associated to reduced transcription when CSA is affected and abnormal ribosomal transcript accumulation after FECH silencing. Accordingly, primary fibroblasts from CS and EPP fibroblasts show opposed amount of total rRNAs. After cell irradiation with UV light, CSA triggers the dissociation of the CSA-FECH-RNAP1-RPs complex from the chromatin while it stabilizes its binding to FECH. Besides disclosing a function for FECH within nucleoli, this study sheds light on the still unknown mechanisms through which CSA modulates rRNA transcription.

2021-10-11 | PXD023472 | Pride

Gene expression regulated by CSA and CSB in neuroblastoma cell line

Project description:Mutations in the CSA and CSB genes are causative of Cockayne syndrome neurological disorder. Since the identification of the indispensable functions of these two proteins in transcription-coupled repair and restoring RNA synthesis following DNA damage, the paradoxical milder clinical spectrum in CS-A patients has been puzzling. In this study we compared the effect of a CSA and a CSB defect at the levels of the cell and the intact organism. We showed that CSA-deficient zebrafish embryos exhibited modest hypersensitive to UV damage than CSB depletion. We found that loss of CSA can effectively release aggregation of mutant crystallin proteins in vitro. We described the distinct effect of CSA and CSB on neuritogenesis and elucidated the differentiated gene expression pathways regulated by these two proteins. Our data demonstrate convergent and divergent roles for CSA and CSB in DNA repair and transcription regulation and provide explanations for the reported differences between CS-A and CS-B patients.

2019-03-29 | GSE129002 | GEO

Cockayne syndrome A and B proteins regulate the transcription arrest upon genotoxic stress through a ubiquitin/proteasome degradation process (ChIP-seq)

Project description:The rare genetic disease Cockayne syndrome (CS) results in mutations in CSA and CSB. Upon UV irradiation, RNA synthesis was arrested: RNA-seq showed 70% of down-regulated genes in common between CSA and CSB deficient cells. ATF3, the product of an immediate early gene was overexpressed and bound to its CRE/ATF site to inhibit its responsive genes. ChIP experiments showed that CSA/CUL4A/DDB1 together with CSB and MDM2, target ATF3. In vivo and in vitro experiments showed that ATF3 was ubiquitilated by a concerted action of CSA and MDM2 ubiquitin-ligases and was further eliminated by the proteasome concomitantly with the recruitment of RNA polymerase II to restart transcription. In CS cells, dysfunctional CSA or CSB were unable to assemble the ubiquitin/proteasome complex, thereby maintaining the ATF3-dependent transcription arrested. Though, in addition to their function in DNA repair, CSA and CSB might thus regulate the timing of DNA binding factors on its specific target site via the ubiquitin/proteasome machinery.

2017-12-01 | GSE87562 | GEO

Cockayne syndrome A and B proteins regulate the transcription arrest upon genotoxic stress through a ubiquitin/proteasome degradation process (RNA-seq)

2017-12-01 | GSE87540 | GEO

Proteome of C. elegans upon NCL-1 or TIF-IA KD during aging

Project description:Anabolic activities such as ribosome biogenesis and protein synthesis are linked to aging. Ribosomal RNA (rRNA) synthesis is the limiting step of ribosome biogenesis, thus dictating the number of ribosomes in cells and, consequently, the capacity for mRNA translation. Knockdown of the rRNA synthesis repressor, NCL-1, accelerated aging, whereas knocking down the transcription initiation factor C36E8.1 promoted longevity. This suggested that rRNA synthesis has a negative correlation with lifespan. To investigate the metabolic changes upon manipulation of rRNA synthesis the proteome of NCL-1 KD and C36E8.1 KD were analyzed at young, middle, and old age (AD2, AD6, AD12).

2024-01-11 | PXD028600 | Pride

DNA methylation of fibroblasts from Cockayne syndrome and UV-sensitivity syndrome patients [EPIC]

Project description:Cockayne syndrome (CS) is a rare genetic disorder caused by mutation of the DNA repair and chromatin remodelling proteins CSA or CSB. Increasing evidences indicate that the progeroid phenotype of CS cannot be solely ascribed to impaired DNA repair, and UV-sensitivity syndrome (UVSS) patients that are also mutated for CSA or CSB do not age prematurely. Epigenetic modifications constitute a hallmark of ageing. We assessed genome-wide DNA methylation (DNAm) at single-nucleotide resolution on fibroblasts derived from CS versus UVSS patients and healthy donors.

2023-12-24 | GSE163840 | GEO

DNA methylation of fibroblasts from Cockayne syndrome and UV-sensitivity syndrome patients [450k]

2023-12-24 | GSE163839 | GEO

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling [Agilent-020186 array]

Project description:Cockayne syndrome (CS) is a rare premature aging disease, which in the majority of cases is caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and die by 12 years of age on average. The CS proteins are involved in transcription and DNA repair, including a specialized form of DNA repair called transcription-coupled nucleotide excision repair (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, likely contributing to the severe premature aging phenotype of this disease. Our cross-species transciptomic analysis in CS postmortem brain tissue, CS mouse and C. elegans models showed that mitochondrial dysfunction is indeed a common feature in CS. Interestingly, the restoration of mitochondrial dysfunction through NAD+ supplementation significantly improved lifespan and healthspan in the C. elegans models of CS, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. We proceeded to perform molecular studies on cerebellar samples obtained from CS patients. We found that these patients exhibited molecular signatures of dysfunctional mitochondrial dynamics that can be corrected with NAD+ supplementation in primary cells with depleted CSA or CSB. Our study provides support for the interconnection between two major aging theories, DNA damage and mitochondrial dysfunction. Together these two agents contribute to an accelerated aging program that can be averted by NAD+ supplementation.

2020-12-22 | GSE144556 | GEO

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling [HumanHT-12 V4.0]

2020-12-22 | GSE144557 | GEO

Gloable gene expression is affected by loss of CSB function in the rat model for Cockayne syndrome

Project description:Cockayne syndrome (CS) is a rare genetic neurodevelopmental disorder, characterized by a deficiency in the transcription-coupled nucleotide excision repair pathway. Mutation of Cockayne syndrome B (CSB) affects basal transcription which is considered a major cause of CS neurological dysfunction. Here, we generated a rat model by mimicking a nonsense mutation in the CSB(ERCC6) gene of CS-B patients. CSB-deficient rats exhibit the well-known CS repair characteristics: inability to resume RNA synthesis from stalled RNA polymerase II (RNAP II) and persistent gamma H2AX overexpression after UV damage. In contrast to that of the Csb-/- mouse models, the cerebella of the CSB-deficient rats are more profoundly affected. Both the molecular and the granular layers of the cerebellum cortex showed significant atrophy. The white matter of the cerebellum demonstrated high GFAP staining indicative of reactive astrogliosis. RNA-seq analysis of CSB-deficient rat cerebella revealed that even in the absence of UV damage, CSB affects the expression of hundreds of genes, many of which are neuronal genes, suggesting that transcription dysregulation could contribute to the neurological features in CSB rat models.

2019-02-05 | GSE126032 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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