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

Ingrid Van Der Pluijm,Susan W Wijnhoven,Susana Velasco,Gijsbertus T J Van Der Horst,Karin E M Diderich,Errol C Friedberg,Theo G M F Gorgels,Conny Van Oostrom,Harry Van Steeg,Renata M C Brandt,Jan H J Hoeijmakers,James R Mitchell,Kiyoji Tanaka,Rudolf Beems,Laura J Niedernhofer,Jan De Wit,George A Garinis,Priscilla Cooper

doi:10.1371/journal.pbio.0050002

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 Csbm/m/Xpa−/− mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csbm/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 Csbm/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.

Highlights

A prevailing hypothesis to explain the molecular basis of ageing is Harman’s ‘‘free-radical theory of ageing’’, which states that endogenous reactive oxygen species (ROS), which result from cellular metabolism, continually damage biomolecules [1]
DNA damage is typically kept in check by a variety of enzymes, several premature ageing disorders result from failure to remove damage from active genes
Patients with Cockayne syndrome (CS), a genetic mutation affecting one class of DNA repair enzymes, display severe growth retardation, neurological symptoms, and signs of premature ageing followed by an early death

Summary

Introduction

A prevailing hypothesis to explain the molecular basis of ageing is Harman’s ‘‘free-radical theory of ageing’’, which states that endogenous reactive oxygen species (ROS), which result from cellular metabolism, continually damage biomolecules [1]. In line with this hypothesis, it has been shown that increased resistance to oxidative stress (e.g., by improved antioxidant defense) extends the lifespan of Caenorhabditis elegans, Drosophila, and rodents [2,3,4], whereas hypersensitivity to oxygen considerably reduces the lifespan of nematodes [5]. Available evidence suggests that CS cells are defective in TCR of non–helix distorting DNA lesions that block transcription such as transcription-blocking oxidative DNA lesions [11,12], which are normally genome-

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