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Gene expression responses to DNA damage are altered in human aging and in Werner Syndrome

Oncogene volume 24, pages 5026–5042 (2005)Cite this article

Abstract

The accumulation of DNA damage and mutations is considered a major cause of cancer and aging. While it is known that DNA damage can affect changes in gene expression, transcriptional regulation after DNA damage is poorly understood. We characterized the expression of 6912 genes in human primary fibroblasts after exposure to three different kinds of cellular stress that introduces DNA damage: 4-nitroquinoline-1-oxide (4NQO), γ-irradiation, or UV-irradiation. Each type of stress elicited damage specific gene expression changes of up to 10-fold. A total of 85 genes had similar changes in expression of 3–40-fold after all three kinds of stress. We examined transcription in cells from young and old individuals and from patients with Werner syndrome (WS), a segmental progeroid condition with a high incidence of cancer, and found various age-associated transcriptional changes depending upon the type of cellular stress. Compared to young individuals, both WS and old individuals had similarly aberrant transcriptional responses to γ- and UV-irradiation, suggesting a role for Werner protein in stress-induced gene expression. Our results suggest that aberrant DNA damage-induced gene regulation may contribute to the aging process and the premature aging in WS.

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Abbreviations

WS:

Werner syndrome

CV:

coefficient of variation

EST:

expressed sequence Tag

4-NQO:

4-nitroquinoline-1-oxide

H-ESR:

human environmental stress response

PDL:

population doubling

IE:

immediate-early gene

GO:

gene ontology™

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Acknowledgements

This work was supported by the Danish Center for Molecular Gerontology, Aarhus Universitets Forskningsfond (E-2002-SUN-3-11), Lundbeckfonden (117/02), and The Danish Cancer Society (DS 04 024). We thank members of the laboratory for reading and comments.

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Authors and Affiliations

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

    Kasper J Kyng, Alfred May & Vilhelm A Bohr

  2. Department of Molecular Biology, Danish Center for Molecular Gerontology, University of Aarhus, DK-8000 Aarhus C, Denmark

    Kasper J Kyng & Tinna Stevnsner

  3. Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, 21224, MD, USA

    Kevin G Becker

  4. Institute for Human Genetics, University of Aarhus, Denmark

    Steen Kølvrå

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  1. Kasper J Kyng
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Correspondence to Vilhelm A Bohr.

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Kyng, K., May, A., Stevnsner, T. et al. Gene expression responses to DNA damage are altered in human aging and in Werner Syndrome. Oncogene 24, 5026–5042 (2005). https://doi.org/10.1038/sj.onc.1208692

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