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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE87540 | GEO | 2017/12/01

SECONDARY ACCESSION(S): PRJNA345197

REPOSITORIES: GEO

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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

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

Project description: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.

2020-03-16 | GSE122736 | GEO

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

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

TRiC controls transcription resumption after UV damage by regulating Cockayne Syndrome protein A

Project description:Transcription-blocking DNA lesions are removed by transcription-coupled nucleotide excision repair (TC-NER) to preserve cell viability. TC-NER is triggered by the stalling of RNA polymerase II at DNA lesions, leading to the recruitment of TC-NER-specific factors such as the CSA-DDB1-CUL4A-RBX1 cullin-RING ubiquitin ligase complex (CRLCSA). Despite its vital role in TC-NER, little is known about the regulation of the CRLCSA complex during TC-NER. Using conventional and cross-linking immunoprecipitations coupled to mass spectrometry, we uncover a stable interaction between CSA and the TRiC chaperonin. TRiC’s binding to CSA ensures its stability and DDB1-dependent assembly into the CRLCSA complex. Consequently, loss of TRiC leads to mislocalization and depletion of CSA, as well as impaired transcription recovery following UV damage, suggesting defects in TC-NER. Furthermore, Cockayne syndrome (CS)-causing mutations in CSA lead to increased TRiC binding and a failure to compose the CRLCSA complex. Thus, we uncover CSA as a novel TRiC substrate and reveal a role for TRiC in regulating CSA-dependent TC-NER and the development of CS.

2018-05-02 | PXD008868 | Pride

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

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 | GSE144557 | GEO

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

2020-12-22 | GSE144556 | GEO

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

Transcription-coupled DNA-Protein Crosslink repair by CSB and CRL4(CSA)-mediated degradation

Project description:DNA-protein crosslinks (DPCs), arise from enzymatic intermediates, endogenous metabolism or exogenous chemicals like chemotherapeutics. DPCs are highly cytotoxic as they will impede DNA transacting processes such as replication, which is counteracted by proteolysis-mediated DPC removal by the protease SPRTN or the proteasome. However, how DPCs affect transcription and how transcription-blocking DPCs are repaired remains largely unknown. Here, we show that DPCs severely inhibit RNA polymerase II (Pol II)-mediated transcription, resulting in the recruitment of the transcription-coupled nucleotide excision repair (TC-NER) factors CSA and CSB. Interestingly, CSA and CSB are indispensable for transcription-coupled DPC (TC-DPC) repair, while the downstream TC-NER factors UVSSA and XPA are not, indicative of a non-canonical TC-NER mechanism. TC-DPC repair functions independent of SPRTN, but is mediated by the activities of the ubiquitin ligase CRL4CSA and the proteasome. Thus, DPCs are preferentially repaired in genes by a dedicated transcription-coupled repair mechanism, which is crucial to warrant correct transcription.

2024-02-09 | PXD041679 | Pride

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