The transcriptional response after oxidative stress is defective in Cockayne syndrome group B cells

Kyng, Kasper Jacobsen; May, Alfred; Brosh, Robert M.; Cheng, Wen‐Hsing; Chen, Catheryne; Becker, Kevin G.; Bohr, Vilhelm A.

doi:10.1038/sj.onc.1206187

Cited by 63 publications

(49 citation statements)

References 52 publications

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“…It has been hypothesized that CSB would induce transcription of genes encoding DNA glycosylases such as OGG1 (Dianov et al, 1999;Tuo et al, 2002). Suggestion of a defect in the transcriptional response of CS-B cells after H 2 O 2 treatment has been provided (Kyng et al, 2003) and a recent study demonstrates that CSB is involved in the regulation of the transcriptional program after UV damage (Proietti-De-Santis et al, 2006). It would be interesting to analyse further the role of CS proteins in transcription regulation after oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

The role of CSA in the response to oxidative DNA damage in human cells

et al. 2007

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Cockayne syndrome (CS) is a rare genetic disease characterized by severe growth, mental retardation and pronounced cachexia. CS is most frequently due to mutations in either of two genes, CSB and CSA. Evidence for a role of CSB protein in the repair of oxidative DNA damage has been provided recently. Here, we show that CSA is also involved in the response to oxidative stress. CS-A human primary fibroblasts and keratinocytes showed hypersensitivity to potassium bromate, a specific inducer of oxidative damage. This was associated with inefficient repair of oxidatively induced DNA lesions, namely 8-hydroxyguanine (8-OH-Gua) and (5 0 S)-8,5 0 -cyclo 2 0 -deoxyadenosine. Expression of the wild-type CSA in the CS-A cell line CS3BE significantly decreased the steady-state level of 8-OH-Gua and increased its repair rate following oxidant treatment. CS-A cell extracts showed normal 8-OH-Gua cleavage activity in an in vitro assay, whereas CS-B cell extracts were confirmed to be defective. Our data provide the first in vivo evidence that CSA protein contributes to prevent accumulation of various oxidized DNA bases and underline specific functions of CSB not shared with CSA. These findings support the hypothesis that defective repair of oxidative DNA damage is involved in the clinical features of CS patients.

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Section: Discussionmentioning

confidence: 99%

The role of CSA in the response to oxidative DNA damage in human cells

et al. 2007

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“…CSB stimulates transcription by stimulating elongation of actively transcribing RNA polymerase bound to DNA and nascent RNA (Selby and Sancar, 1997a;Tantin et al, 1997;. Furthermore, using array analysis, Kyng et al (Kyng et al, 2003) demonstrated that the transcriptional response after oxidative stress is defective in CSB cells. Some of the major defects were found to be in the transcription of genes involved in DNA repair, signal transduction and ribosomal functions.…”

Section: The Role Of Csb In Various Cellular Processesmentioning

confidence: 99%

“…There has been considerable discussion about whether the complex clinical phenotype of CS is due to a primary defect in DNA repair or transcription. Much data including array analysis by Kyng et al (Kyng et al, 2003) would suggest that a major defect in this disease lies in the transcriptional response to oxidative stress. This is compatible with the substantial amounts of data suggesting that progeria in CS is linked to accumulated endogenous DNA damage (Andressoo et al, 2006).…”

Section: The Role Of Csb In Dna Repair -And Consequences For the Aginmentioning

confidence: 99%

The role of Cockayne Syndrome group B (CSB) protein in base excision repair and aging

Stevnsner

Müftüoğlu

Aamann

et al. 2008

Mechanisms of Ageing and Development

124

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Cockayne Syndrome (CS) is a rare human genetic disorder characterized by progressive multisystem degeneration and segmental premature aging. The CS complementation group B (CSB) protein is engaged in transcription coupled and global nucleotide excision repair, base excision repair and general transcription. However, the precise molecular function of the CSB protein is still unclear. In the current review we discuss the involvement of CSB in some of these processes, with focus on the role of CSB in repair of oxidative damage, as deficiencies in the repair of these lesions may be an important aspect of the premature aging phenotype of CS.

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“…Mutations in XPB and XPD affect specific expression of nuclear hormone receptors that are important in development including the retinoic acid receptors RARalpha, ERalpha, and AR (Keriel et al, 2002), which may account for part of the wasting phenotype of XP/CS patients. Microarray analysis of CSB cells has detected multiple changes in gene expression associated with the response to oxidative stress, signal transduction, ribosomal synthesis and uracil-Dglycosylase (Kyng et al, 2003). We have also found several specific gene expression markers of CSB in a microarray analysis that compared parent child pairs from CS-B families (Hefner et al, 2006).…”

Section: Csa (Ercc8)mentioning

confidence: 75%

Cockayne syndrome exhibits dysregulation of p21 and other gene products that may be independent of transcription-coupled repair

et al. 2007

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Cockayne syndrome (CS) is a progressive childhood neurodegenerative disorder associated with a DNA repair defect caused by mutations in either of two genes, CSA and CSB. These genes are involved in nucleotide excision repair (NER) of DNA damage from ultraviolet (UV) light, other bulky chemical adducts and reactive oxygen in transcriptionally active genes (transcription coupled repair, TCR). For a long period it has been assumed that the symptoms of CS patients are all due to reduced TCR of endogenous DNA damage in the brain, together with unexplained unique sensitivity of specific neural cells in the cerebellum. Not all the symptoms of CS patients are however easily related to repair deficiencies, so we hypothesize that there are additional pathways relevant to the disease, particularly those that are downstream consequences of a common defect in the E3 ubiquitin ligase associated with the CSA and CSB gene products. We have found that the CSB defect results in altered expression of anti-angiogenic and cell cycle genes and proteins at the level of both gene expression and protein lifetime. We find an over-abundance of p21 due to reduced protein turnover, possibly due to the loss of activity of the CSA/CSB E3 ubiquitylation pathway. Increased levels of p21 can result in growth inhibition, reduced repair from the p21-PCNA interaction, and increased generation of reactive oxygen. Consistent with increased reactive ozygen levels we find that CS-A and -B cells grown under ambient oxygen show increased DNA breakage, as compared to xeroderma pigmentosum cells. Thus the complex symptoms of CS may be due to multiple, independent downstream targets of the E3 ubiquitylation system that results in increased DNA damage, reduced transcription coupled repair, and inhibition of cell cycle progression and growth.

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The transcriptional response after oxidative stress is defective in Cockayne syndrome group B cells

Cited by 63 publications

References 52 publications

The role of CSA in the response to oxidative DNA damage in human cells

The role of CSA in the response to oxidative DNA damage in human cells

The role of Cockayne Syndrome group B (CSB) protein in base excision repair and aging

Cockayne syndrome exhibits dysregulation of p21 and other gene products that may be independent of transcription-coupled repair

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