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Impaired Genome Maintenance Suppresses the Growth Hormone–Insulin-Like Growth Factor 1 Axis in Mice with Cockayne Syndrome

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 mim...

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Detalles Bibliográficos
Autores principales: 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
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1698505/
https://www.ncbi.nlm.nih.gov/pubmed/17326724
http://dx.doi.org/10.1371/journal.pbio.0050002
Descripción
Sumario: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.