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 stressinducing 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.

Histone H3.3 maintains genome integrity during mammalian development

“…Loss of ATRX leads to centromere instability and aneuploidy in mouse oocytes and preimplantation embryos (Baumann et al 2010). ATRX deficiency by conditional knockouts in neuronal cell lineages or RNAi knockdown in cultured cells induced cell death, telomere dysfunction, and prolonged mitosis, with defects including anaphase bridges and lagging chromosomes (Ritchie et al 2008;Watson et al 2013). These are the same defects that we observed in the H3.3 knockout MEFs.…”

The Polycomb Repressive Complex 1 Protein BMI1 Is Required for Constitutive Heterochromatin Formation and Silencing in Mammalian Somatic Cells

“…It is thus notable that Bmi1-deficient mice show reduced lifespan, genomic instability, neurodegeneration, and progeria features (38,(42)(43)(44)(45)75). Similar anomalies were also reported for ATRxdeficient mice (18,20). Taken together, this raises the possibility that BMI1 requirement for constitutive heterochromatin formation and silencing could underlie the premature aging/ senescence and genomic instability phenotypes observed in Bmi1-null mice and cells.…”

Genetic Inactivation of ATRX Leads to a Decrease in the Amount of Telomeric Cohesin and Level of Telomere Transcription in Human Glioma Cells

“…ATRX enrichment has been previously reported at subtelomeres and telomeres of human primary cells and mouse embryonic stem cells (37,38). More recently, Atrxnull mouse embryonic brain cells were shown to exhibit telomeric damage that could be worsened by treatment with the G-quadruplex ligand telomestatin, suggesting a role for ATRX in the replication of telomeric G4-DNA structures (39). In mouse embryonic stem cells, ATRX and H3.3 colocalized within PML bodies containing telomeric DNA (40).…”

“…Alternatively, the present, as well as the recent (35), findings that ATRX inactivation diminished TERRA levels might be explained by the occurrence of a concomitant loss of control of histone/DNA methylation at the subtelomeres. Indeed, in mouse embryonic stem cells, disruption of ATRX/H3.3 binding led to a loss of control of the telomeric histone methylation pattern (39), and in human cells, TERRA abundance is negatively regulated by methylation of TERRA promoter CpG islands (41). Of note, it was recently reported that genetic inactivation of ATRX led to persistence of both TERRA and RPA foci at telomeres of HeLa cells in G 2 /M, suggesting a role for ATRX in cell cycle-dependent regulation of TERRA abundance at telomeres (42).…”