title: Gene expression responses to DNA damage are altered in human aging and in Werner Syndrome.
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), gamma-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 gamma- 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.
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
authors.forename: Kasper J
authors.initials: KJ
authors.lastname: Kyng
authors.forename: Alfred
authors.initials: A
authors.lastname: May
authors.forename: Tinna
authors.initials: T
authors.lastname: Stevnsner
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.forename: Steen
authors.initials: S
authors.lastname: Kølvrå
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics*; D002460:Cell Line; D004249:DNA Damage / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005720:Gamma Rays; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D017781:Genes, Immediate-Early / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D015363:Quinolones / Q000494:pharmacology; D012867:Skin / Q000166:cytology; D013312:Stress, Physiological; D014466:Ultraviolet Rays; D014898:Werner Syndrome / Q000235:genetics*
chemical_list: C120195:4-nitroquinolone-1-oxide; D015363:Quinolones; D015112:4-Nitroquinoline-1-oxide