PUMILIO hyperactivity drives premature aging of Norad-deficient mice.
Elife
; 82019 02 08.
Article
em En
| MEDLINE
| ID: mdl-30735131
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 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.
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Base de dados:
MEDLINE
Assunto principal:
Envelhecimento
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Proteínas de Ligação a RNA
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Senilidade Prematura
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RNA Longo não Codificante
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article