title: Atrx deficiency induces telomere dysfunction, endocrine defects, and reduced life span.
abstract: Human ATRX mutations are associated with cognitive deficits, developmental abnormalities, and cancer. We show that the Atrx-null embryonic mouse brain accumulates replicative damage at telomeres and pericentromeric heterochromatin, which is exacerbated by loss of p53 and linked to ATM activation. ATRX-deficient neuroprogenitors exhibited higher incidence of telomere fusions and increased sensitivity to replication stress-inducing drugs. Treatment of Atrx-null neuroprogenitors with the G-quadruplex (G4) ligand telomestatin increased DNA damage, indicating that ATRX likely aids in the replication of telomeric G4-DNA structures. Unexpectedly, mutant mice displayed reduced growth, shortened life span, lordokyphosis, cataracts, heart enlargement, and hypoglycemia, as well as reduction of mineral bone density, trabecular bone content, and subcutaneous fat. We show that a subset of these defects can be attributed to loss of ATRX in the embryonic anterior pituitary that resulted in low circulating levels of thyroxine and IGF-1. Our findings suggest that loss of ATRX increases DNA damage locally in the forebrain and anterior pituitary and causes tissue attrition and other systemic defects similar to those seen in aging.
authors.affiliation: Children’s Health Research Institute, London, Ontario, Canada.
authors.forename: L Ashley
authors.initials: LA
authors.lastname: Watson
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Solomon
authors.forename: Jennifer Ruizhe
authors.initials: JR
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Matthew
authors.initials: M
authors.lastname: Edwards
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shin-ya
authors.forename: Frank
authors.initials: F
authors.lastname: Beier
authors.forename: Nathalie G
authors.initials: NG
authors.lastname: Bérubé
mesh_terms: D000375:Aging; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D003072:Cognition Disorders / Q000235:genetics; D004249:DNA Damage; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D054856:G-Quadruplexes; D005838:Genotype; D006570:Heterochromatin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008024:Ligands; D008136:Longevity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence / Q000379:methods; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D010080:Oxazoles / Q000494:pharmacology; D010641:Phenotype; D013234:Stem Cells / Q000166:cytology; D016615:Telomere / Q000648:ultrastructure*; D013974:Thyroxine / Q000378:metabolism; D000075924:X-linked Nuclear Protein
chemical_list: D006570:Heterochromatin; D008024:Ligands; D009687:Nuclear Proteins; D010080:Oxazoles; C431888:telomestatin; D007334:Insulin-Like Growth Factor I; D004265:DNA Helicases; C490462:Atrx protein, mouse; D000075924:X-linked Nuclear Protein; D013974:Thyroxine
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