Nihei Y, Mori K, Werner G, et al. - Researchers examined the relation of hnRNPA3 expression, RNA foci formation, dipeptide-repeat protein (DPR) production, and DNA damage in cultured cells, including patient-derived human neurons and brains of C9orf72 carriers and illustrated that hnRNPA3 also binds to the antisense repeat RNA. Both DPR production and deposition from sense and antisense RNA repeats are raised upon hnRNPA3 decline. All DPRs induced DNA double-strand breaks (DSB), which was considerably improved upon a decrease of hnRNPA3. Foci formed by phosphorylated Ataxia Telangiectasia Mutated (pATM) was raised by poly-glycine–arginine, and poly-proline-arginine, which is a major sensor of DSBs, whereas poly-glycine–alanine (poly-GA) elicited a decrease of pATM foci. Lower nuclear hnRNPA3 levels were related to progressed DNA damage in dentate gyri of C9orf72 individuals. Furthermore, improved poly-GA deposition related to decreased pATM foci. As cytoplasmic pATM deposits partly colocalized with poly-GA deposits, these outcomes imply that poly-GA, the most prevalent DPR seen in C9orf72 individuals, differentially results in DNA damage and that poly-GA selectively sequesters pATM in the cytoplasm hindering its admission to sites of DNA damage. Therefore, the mislocalization of nuclear hnRNPA3 caused by poly-GA results in progressed production of poly-GA, which, in turn, partly depletes pATM, and consequently improves DSB.