Genomic localization of Cockayne syndrom B protein upon genotoxic stresses
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Jieun Jeong
PROVIDER: E-GEOD-50925 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Cockayne syndrome is an inherited premature aging syndrome associated with developmental and neurological disorders. Mutations in the genomic locus encoding CSB are associated with 80% Cockayne syndrome cases. Transcription profiling assays reveal the association of mis-regulation of gene expression with Cockayne syndrome, highlighting the importance of CSB in transcription regulation. However, many questions remain unanswered as how CSB regulates transcription. In this study, we dissect the mechanisms by which CSB regulates transcription during normal growth. By anti-CSB chromatin immunoprecipitation followed by deep sequencing, we found CSB is enriched at genomic regions containing TGASTCA motifs, to which the immediate early gene product C-Jun binds specifically. We further demonstrate that c-Jun co-immunoprecipitates with CSB. In addition, the targeting of CSB to genomic region containing TGASTCA motifs was drastically reduced in cells treated c-Jun shRNA. Reverse transcription followed by quantitative PCR indicates that CSB can regulate gene expression nearby its binding sites, both in activation and repression. The remodeling defective CSBM-bM-^HM-^FN1 mutant is also targeted to TGASTCA motifs, but cannot always substitute CSB function in transcription regulating, suggesting the importance of remodeling by CSB in transcription regulation. Notably, the Cockayne syndrome related mutation encoding protein CSBR670W, which is defective in ATP hydrolysis but is targeted to TGASTCA motifs efficiently, indicating that ATP hydrolysis is dispensable for c-Jun mediated CSB targeting, in sharp contrast to the ATP-dependent targeting mechanism by which CSB is relocated to DNA lesion stalled transcription. Together, these results reveal a second CSB targeting mechanism in which DNA sequence specific transcription factor c-Jun targets CSB to specific genomic region and regulate gene expression. Genomic localization of CSB and remodeling deficient CSBM-bM-^HM-^FN1
2014-03-06 | E-GEOD-50171 | biostudies-arrayexpress
Project description:The CSB-PGBD3 fusion protein arose over 43 million years ago when a 2.5 kb piggyBac 3 (PGBD3) transposon inserted into intron 5 of the Cockayne syndrome Group B (CSB) gene in the common ancestor of all higher primates. The CSB-PGBD3 fusion protein binds internally-deleted PGBD3 elements called MER85s in vitro, and induces a strong interferon-like innate antiviral immune response when expressed in CSB-null UVSS1KO cells. To explore the connection between DNA binding and gene expression changes induced by CSB-PGBD3, we investigated the genome-wide DNA binding profile of the fusion protein. 1 ChIP sample and 1 unenriched input control from the same crosslinked chromatin pool
2012-07-10 | E-GEOD-37919 | biostudies-arrayexpress
Project description:Cockayne syndrome is an inherited premature aging syndrome associated with developmental and neurological disorders. Mutations in the genomic locus encoding CSB are associated with 80% Cockayne syndrome cases. CSB is invovled in relieving UV-induced and oxidative stree. To gain more insights into the fucntion of CSB under these stress, we use ChIP-seq to determine the genomic localization of CSB 1 hour after UV irradiation and menadione treatment.
2015-11-09 | GSE50925 | GEO
Project description:Cockayne syndrome is an inherited premature aging syndrome associated with developmental and neurological disorders. Mutations in the genomic locus encoding CSB are associated with 80% Cockayne syndrome cases. Transcription profiling assays reveal the association of mis-regulation of gene expression with Cockayne syndrome, highlighting the importance of CSB in transcription regulation. However, many questions remain unanswered as how CSB regulates transcription. In this study, we dissect the mechanisms by which CSB regulates transcription during normal growth. By anti-CSB chromatin immunoprecipitation followed by deep sequencing, we found CSB is enriched at genomic regions containing TGASTCA motifs, to which the immediate early gene product C-Jun binds specifically. We further demonstrate that c-Jun co-immunoprecipitates with CSB. In addition, the targeting of CSB to genomic region containing TGASTCA motifs was drastically reduced in cells treated c-Jun shRNA. Reverse transcription followed by quantitative PCR indicates that CSB can regulate gene expression nearby its binding sites, both in activation and repression. The remodeling defective CSB∆N1 mutant is also targeted to TGASTCA motifs, but cannot always substitute CSB function in transcription regulating, suggesting the importance of remodeling by CSB in transcription regulation. Notably, the Cockayne syndrome related mutation encoding protein CSBR670W, which is defective in ATP hydrolysis but is targeted to TGASTCA motifs efficiently, indicating that ATP hydrolysis is dispensable for c-Jun mediated CSB targeting, in sharp contrast to the ATP-dependent targeting mechanism by which CSB is relocated to DNA lesion stalled transcription. Together, these results reveal a second CSB targeting mechanism in which DNA sequence specific transcription factor c-Jun targets CSB to specific genomic region and regulate gene expression.
2014-03-06 | GSE50171 | GEO
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
Project description:SUMOylation is a posttranslational protein modification which is characterized by the covalent attachment of a small 11kDa protein, called Small Ubiquitin-like MOdifier (SUMO). SUMOylation plays a pivotal role in a multitude of cellular pathways including cellular responses upon DNA damage. Here, we identified multiple proteins which are SUMOylated in U2OS cells in response to ultraviolet light (UV) irradiation and ionizing radiation (IR). We show that the SUMOylation response upon UV irradiation was more pronounced compared to the response upon IR. The major SUMOylation target upon UV-irradiation was the transcription-coupled nucleotide excision repair (TC-NER) protein, Cockayne Syndrome B (CSB). This protein plays an important role in the repair of UV-induced lesions in actively transcribed genes. In a second proteomic approach we identified SUMOylation-dependent and independent protein interactors of the N-terminus of CSB. Here, we uncovered that the affinity of multiple RNA polymerase-associated proteins towards CSB is influenced by SUMOylation. Finally, we set out to identify ubiquitination events upon UV-irradiation which are influenced by the CSA-ubiquitin ligase complex, which is also involved in TC-NER and is closely connected to CSB, because mutations in either CSA or CSB result in the same phenotype, Cockayne syndrome. We found that RPB1, the major subunit of RNA polymerase II, was ubiquitinated in a CSA-dependent manner upon UV which finally led to its degradation.
2019-10-11 | PXD010609 | Pride
Project description:Cockayne syndrome is a segmental progeria most often caused by mutations in the CSB gene encoding a SWI/SNF-like ATPase required for transcription-coupled DNA repair (TCR). Over 43 Mya before marmosets diverged from humans, a piggyBac3 (PGBD3) transposable element integrated into intron 5 of the CSB gene. As a result, primate CSB genes now generate both CSB protein and a conserved CSB-PGBD3 fusion protein in which the first 5 exons of CSB are alternatively spliced to the PGBD3 transposase. We show by microarray analysis that expression of the fusion protein alone in CSB-null UV-sensitive syndrome cells (UVSS1KO) cells induces an interferon-like response that resembles both the innate antiviral response and the prolonged interferon response normally maintained by unphosphorylated STAT1 (U-STAT1); moreover, as might be expected based on conservation of the fusion protein, this potentially cytotoxic interferon-like response is largely reversed by coexpression of functional CSB protein. Interestingly, expression of CSB and the CSB-PGBD3 fusion protein together, but neither alone, upregulates the insulin growth factor binding protein IGFBP5 and downregulates IGFBP7, suggesting that the fusion protein may also confer a metabolic advantage, perhaps in the presence of DNA damage. Finally, we show that the fusion protein binds in vitro to members of a dispersed family of 900 internally deleted piggyBac elements known as MER85s, providing a potential mechanism by which the fusion protein could exert widespread effects on gene expression. Our data suggest that the CSB-PGBD3 fusion protein is important in both health and disease, and could play a role in Cockayne syndrome. 12 samples total; 4 gene expression conditions in triplicate; 1 condition is a tag-only negative control
2014-03-20 | E-GEOD-56049 | biostudies-arrayexpress
Project description:We investigated whether transcription-coupled repair deficient mice (Cockayne syndrome B knockout mice (Csb-/-)), known to be sensitive to oxidative stressors, have a different response to ozone than its repair-proficient control, Csb heterozygote (Csb+/-) mice.
2006-11-13 | E-TABM-137 | biostudies-arrayexpress
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