PUMILIO hyperactivity drives premature aging of norad-deficient mice

Florian Kopp, Mahmoud M. Elguindy, Mehmet E. Yalvac, He Zhang, Beibei Chen, Frank A. Gillett, Sungyul Lee, Sushama Sivakumar, Hongtao Yu, Yang Xie, Prashant Mishra, Zarife Sahenk, Joshua T. Mendell

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10 Scopus citations

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.

Original languageEnglish (US)
Article numbere42650
JournaleLife
Volume8
DOIs
StatePublished - Feb 2019

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kopp, F., Elguindy, M. M., Yalvac, M. E., Zhang, H., Chen, B., Gillett, F. A., Lee, S., Sivakumar, S., Yu, H., Xie, Y., Mishra, P., Sahenk, Z., & Mendell, J. T. (2019). PUMILIO hyperactivity drives premature aging of norad-deficient mice. eLife, 8, [e42650]. https://doi.org/10.7554/eLife.42650