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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 Csb(m/m)/Xpa(-/-) mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csb(m/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 Csb(m/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.
- Publication
PLoS biology, 2007, Vol 5, Issue 1, pe2
- ISSN
1545-7885
- Publication type
Journal Article
- DOI
10.1371/journal.pbio.0050002