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The article emphasizes the role of oxidative stress in activating the ATM protein, which is associated with the genetic disorder Ataxia-telangiectasia (A-T). Using cryo-electron microscopy, the study reveals the structural changes in ATM upon activation by hydrogen peroxide (H2O2) and the binding of a p53 substrate peptide, shedding light on the molecular mechanism behind ATM's response to oxidative damage.

PIK3R1 encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β or p110δ. Constitutional PIK3R1 mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous loss-of-function mutations cause SHORT syndrome, featuring insulin resistance and short stature attributed to reduced p110α function, while heterozygous activating mutations cause immunodeficiency, attributed to p110δ activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110α hyperactivation, but do commonly have SHORT syndrome-like features, suggesting p110α hypofunction. We sought to investigate this. In dermal fibroblasts from an APDS2 patient, we found no increased PI3K signalling, with p110δ expression markedly reduced. In preadipocytes, the APDS2 variant was potently dominant negative, associating with Irs1 and Irs2 but failing to heterodimerise with p110α. This attenuation of p110α signalling by a p110δ-activating PIK3R1 variant potentially explains co-incidence of gain-of-function and loss-of-function PIK3R1 phenotypes., Competing Interests: Disclosure and competing interests statement RKS has consulted for Novartis on clinical aspects of PIK3CA-related overgrowth, and for Alnylam, Amryt and AstraZeneca on clinical aspects of monogenic insulin resistance and lipodystrophy