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- Title
Impaired Genome Maintenance Suppresses the Growth Hormone--Insulin-Like Growth Factor 1 Axis in Mice with Cockayne Syndrome.
- Authors
van der Pluijm, Ingrid; Garinis, George A.; Brandt, Renata M. C.; Gorgels, Theo G. M. F.; Wijnhoven, Susan W.; Diderich, Karin E. M.; de Wit, Jan; Mitchell, James R.; van Oostrom, Conny; Beems, Rudolf; Niedernhofer, Laura J.; Velasco, Susana; Friedberg, Errol C.; Tanaka, Kiyoji; van Steeg, Harry; Hoeijmakers, Jan H. J.; van der Horst, Gijsbertus T. J.
- Abstract
Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria that is caused by a defect in the transcription-coupled repair subpathway of nucleotide excision repair (NER). Here, complete inactivation of NER in Csbm/m/Xpa-/- mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csbm/m/Xpa-/- mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the growth hormone/insulin-like growth factor 1 (GH/IGF1) somatotroph axis and oxidative metabolism, increased antioxidant responses, and hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csbm/m/Xpa-/- and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural ageing and the DNA repair-deficient mice. Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis.
- Subjects
DNA repair; DNA damage; PROGERIA; GROWTH factors; RETINAL degeneration; HYPOGLYCEMIA; ANTIOXIDANTS
- Publication
PLoS Biology, 2007, Vol 5, Issue 1, p23
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.0050002