PUMILIO hyperactivity drives premature aging of <i>Norad</i>-deficient mice.

Abstract

Although numerous long noncoding RNAs (lncRNAs) have been identified, our understanding of their roles in mammalian physiology remains limited. Here, we investigated the physiologic function of the conserved lncRNA <i>Norad</i> in vivo. Deletion of <i>Norad</i> in mice results in genomic instability and mitochondrial dysfunction, leading to a dramatic multi-system degenerative phenotype resembling premature aging. Loss of tissue homeostasis in <i>Norad</i>-deficient animals is attributable to augmented activity of PUMILIO proteins, which act as post-transcriptional repressors of target mRNAs to which they bind. <i>Norad</i> is the preferred RNA target of PUMILIO2 (PUM2) in mouse tissues and, upon loss of <i>Norad</i>, PUM2 hyperactively represses key genes required for mitosis and mitochondrial function. Accordingly, enforced <i>Pum2</i> expression fully phenocopies <i>Norad</i> deletion, resulting in rapid-onset aging-associated phenotypes. These findings provide new insights and open new lines of investigation into the roles of noncoding RNAs and RNA binding proteins in normal physiology and aging.