ATM is a Novel Regulator of Nucleolar Transcription

Abstract

ATM (Ataxia‐telangiectasia mutated protein kinase) mediates DNA double‐stranded break (DSB) signaling. ATM deficiency results in the autosomal recessive disorder known as ataxia‐telangiectasia (A‐T). The cause of the neurodegeneration associated with this disorder remains unknown. Here we report the unexpected finding that, in neurons, ATM is a regulator of RNA‐Polymerase‐1 (Pol‐1) ‐mediated transcription of nucleolar rRNA genes (rDNA). Low concentrations of the ATM‐activating DSB inducer, etoposide, stimulated rDNA transcription in both cultured rat cortical neurons and cerebral cortices of postnatal day seven (P7) rats. The etoposide‐mediated activation of rDNA transcription was reduced by ATM inhibition. Importantly, in the absence of etoposide, the specific ATM inhibitor, KU55933, reduced basal levels of nucleolar transcription and attenuated its induction in response to enhanced neuronal activity. Finally, ATM is robustly present in neuronal nucleoli and several critical regulators of Pol‐1 display potential ATM phosphorylation sites. Our results suggests that ATM is a major positive regulator of nucleolar transcription. Hence, defective ribosomal biogenesis may contribute to the A‐T‐associated neurodegeneration.