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 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.
van der Pluijm
Ingrid
I
Department of Genetics, Center for Biomedical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Garinis
George A
GA
Brandt
Renata M C
RM
Gorgels
Theo G M F
TG
Wijnhoven
Susan W
SW
Diderich
Karin E M
KE
de Wit
Jan
J
Mitchell
James R
JR
van Oostrom
Conny
C
Beems
Rudolf
R
Niedernhofer
Laura J
LJ
Velasco
Susana
S
Friedberg
Errol C
EC
Tanaka
Kiyoji
K
van Steeg
Harry
H
Hoeijmakers
Jan H J
JH
van der Horst
Gijsbertus T J
GT
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
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