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

Oncogene volume 22, pages 1135–1149 (2003)Cite this article

Abstract

Cockayne syndrome (CS) is a human hereditary disease belonging to the group of segmental progerias, and the clinical phenotype is characterized by postnatal growth failure, neurological dysfunction, cachetic dwarfism, photosensitivity, sensorineural hearing loss, and retinal degradation. CS-B cells are defective in transcription-coupled DNA repair, base excision repair, transcription, and chromatin structural organization. Using array analysis, we have examined the expression profile in CS complementation group B (CS-B) fibroblasts after exposure to oxidative stress (H2O2) before and after complete complementation with the CSB gene. The following isogenic cell lines were compared: CS-B cells (CS-B null), CS-B cells complemented with wild-type CSB (CS-B wt), and a stably transformed cell line with a point mutation in the ATPase domain of CSB (CS-B ATPase mutant). In the wt rescued cells, we detected significant induction (two-fold) of 112 genes out of the 6912 analysed. The patterns suggested an induction or upregulation of genes involved in several DNA metabolic processes including DNA repair, transcription, and signal transduction. In both CS-B mutant cell lines, we found a general deficiency in transcription after oxidative stress, suggesting that the CSB protein influenced the regulation of transcription of certain genes. Of the 6912 genes, 122 were differentially regulated by more than two-fold. Evidently, the ATPase function of CSB is biologically important as the deficiencies seen in the ATPase mutant cells are very similar to those observed in the CS-B-null cells. Some major defects are in the transcription of genes involved in DNA repair, signal transduction, and ribosomal functions.

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Abbreviations

CS:

cockayne syndrome

CSB:

cockayne syndrome group B

CV:

coefficient of variation

Wt:

wild type CS-B wt CS1AN/pc3.1-CSBwt

CS-B null:

CS1AN/pc3.1

CS-B ATPase mutant:

CS1AN/pc3.1-CSBE646Q

TCR:

transcription-coupled repair

BER:

base excision repair

UDG:

uracil DNA glycosylase

NER:

nucleotide excision repair

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Acknowledgements

We thank Chris Cheadle for statistical help and discussions. Complete results for all genes on the arrays can be found at the following website: http://www.grc.nia.nih.gov/branches/rrb/dna/dnapubs.htm. This work was supported in part by the Danish Center for Molecular Gerontology, the Danish Medical Research Council (9902876), the Danish Cancer Society (9914403 9132/99 14403), Fonden til Lægevidenskabens Fremme and Direktør E Danielsens Fond.

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  1. Kasper J Kyng

    Present address: Department of Molecular and Structural Biology, Danish Center for Molecular Gerontology, University of Aarhus, DK-8000, Aarhus C, Denmark

  2. Contributed equally to this work

Authors and Affiliations

  1. Laboratory of Molecular Gerontology, National Institute on Aging, 5600 Nathan Shock Drive, National Institutes of Health, Baltimore, 21224, MD, USA

    Kasper J Kyng, Alfred May, Robert M Brosh Jr, Wen-Hsing Cheng, Catheryne Chen & Vilhelm A Bohr

  2. DNA Array Unit, National Institute on Aging, National Institutes of Health, Baltimore, 21224, MD, USA

    Kevin G Becker

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Correspondence to Vilhelm A Bohr.

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Kyng, K., May, A., Brosh, R. et al. The transcriptional response after oxidative stress is defective in Cockayne syndrome group B cells. Oncogene 22, 1135–1149 (2003). https://doi.org/10.1038/sj.onc.1206187

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