The cGAS-STING, p38 MAPK, and p53 pathways link genome instability to accelerated cellular senescence in ATM-deficient murine lung fibroblasts.

Ataxia-telangiectasia (A-T) is a pleiotropic genome instability syndrome resulting from the loss of the homeostatic protein kinase ATM. The complex phenotype of A-T includes progressive cerebellar degeneration, immunodeficiency, gonadal atrophy, interstitial lung disease, cancer predisposition, endocrine abnormalities, chromosomal instability, radiosensitivity, and segmental premature aging. Cultured skin fibroblasts from A-T patients exhibit premature senescence, highlighting the association between genome instability, cellular senescence, and aging.

Accelerated replicative senescence of ataxia-telangiectasia skin fibroblasts is retained at physiologic oxygen levels, with unique and common transcriptional patterns.

The genetic disorder, ataxia-telangiectasia (A-T), is caused by loss of the homeostatic protein kinase, ATM, and combines genome instability, tissue degeneration, cancer predisposition, and premature aging. Primary fibroblasts from A-T patients exhibit premature senescence when grown at ambient oxygen concentration (21%). Here, we show that reducing oxygen concentration to a physiological level range (3%) dramatically extends the proliferative lifespan of human A-T skin fibroblasts.

Pathogenic variant-based preconception carrier screening in the Israeli Jewish population.

Preconception carrier screening allows identification of couples at risk to have offspring with autosomal recessive and X-linked disorders. In a current multiethnic world, screening based on self-reported ancestry has limitations. Here we describe the findings of a comprehensive pan-ethnic variant-based carrier screening, using the Israeli Jewish population as a model.