title: 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.affiliation: Department of Genetics, Center for Biomedical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: van der Pluijm
authors.forename: George A
authors.initials: GA
authors.lastname: Garinis
authors.forename: Renata M C
authors.initials: RM
authors.lastname: Brandt
authors.forename: Theo G M F
authors.initials: TG
authors.lastname: Gorgels
authors.forename: Susan W
authors.initials: SW
authors.lastname: Wijnhoven
authors.forename: Karin E M
authors.initials: KE
authors.lastname: Diderich
authors.forename: Jan
authors.initials: J
authors.lastname: de Wit
authors.forename: James R
authors.initials: JR
authors.lastname: Mitchell
authors.forename: Conny
authors.initials: C
authors.lastname: van Oostrom
authors.forename: Rudolf
authors.initials: R
authors.lastname: Beems
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Niedernhofer
authors.forename: Susana
authors.initials: S
authors.lastname: Velasco
authors.forename: Errol C
authors.initials: EC
authors.lastname: Friedberg
authors.forename: Kiyoji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
mesh_terms: D000375:Aging; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003057:Cockayne Syndrome / Q000209:etiology / Q000235:genetics*; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004051:Diethylhexyl Phthalate / Q000494:pharmacology; D005227:Fatty Acids / Q000096:biosynthesis; D016678:Genome / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D013006:Growth Hormone / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000075223:Poly-ADP-Ribose Binding Proteins; D011839:Radiation, Ionizing; D052683:Somatotrophs / Q000378:metabolism; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics
chemical_list: D000975:Antioxidants; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D000075223:Poly-ADP-Ribose Binding Proteins; D051760:Xeroderma Pigmentosum Group A Protein; C501002:Xpc protein, mouse; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D004051:Diethylhexyl Phthalate; C513075:Ercc6 protein, mouse; D045643:DNA Repair Enzymes; D005947:Glucose