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

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.

• 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
• Journal: PLoS biology (PLoS Biol) Vol. 5 Issue 1 Pg. e2 (Jan 2007) ISSN: 1545-7885 [Electronic] United States
• PMID: 17326724 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• DNA-Binding Proteins
• Fatty Acids
• Poly-ADP-Ribose Binding Proteins
• Xeroderma Pigmentosum Group A Protein
• Xpc protein, mouse
• Insulin-Like Growth Factor I
• Growth Hormone
• Diethylhexyl Phthalate
• Ercc6 protein, mouse
• DNA Repair Enzymes
• Glucose

Topics

• Aging
• Animals
• Antioxidants (pharmacology)
• Cockayne Syndrome (etiology, genetics)
• DNA Repair
• DNA Repair Enzymes (genetics)
• DNA-Binding Proteins (genetics)
• Diethylhexyl Phthalate (pharmacology)
• Fatty Acids (biosynthesis)
• Genome (genetics)
• Glucose (metabolism)
• Growth Hormone (genetics)
• Insulin-Like Growth Factor I (genetics, metabolism)
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Poly-ADP-Ribose Binding Proteins
• Radiation, Ionizing
• Somatotrophs (metabolism)
• Xeroderma Pigmentosum Group A Protein (genetics)