Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome.

• Main Authors: Ingrid van der Pluijm, George A Garinis, Renata M C Brandt, Theo G M F Gorgels, Susan W Wijnhoven, Karin E M Diderich, Jan de Wit, James R Mitchell, Conny van Oostrom, Rudolf Beems, Laura J Niedernhofer, Susana Velasco, Errol C Friedberg, Kiyoji Tanaka, Harry van Steeg, Jan H J Hoeijmakers, Gijsbertus T J van der Horst
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2007-01-01
• Series: PLoS Biology
• Online Access: http://europepmc.org/articles/PMC1698505?pdf=render

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.