Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
Mehmet E Yalvac
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, United States; Department of Neurology, The Ohio State University, Columbus, United States
He Zhang
Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, United States; Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, United States
Beibei Chen
Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, United States; Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, United States
Frank A Gillett
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States
Yang Xie
Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, United States; Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, United States; Harold C Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
Prashant Mishra
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United States
Zarife Sahenk
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, United States; Department of Pediatrics, The Ohio State University, Columbus, United States; Department of Neurology, The Ohio State University, Columbus, United States
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States; Harold C Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States
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 Norad in vivo. Deletion of Norad 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 Norad-deficient animals is attributable to augmented activity of PUMILIO proteins, which act as post-transcriptional repressors of target mRNAs to which they bind. Norad is the preferred RNA target of PUMILIO2 (PUM2) in mouse tissues and, upon loss of Norad, PUM2 hyperactively represses key genes required for mitosis and mitochondrial function. Accordingly, enforced Pum2 expression fully phenocopies Norad 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.
