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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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)
JournaleLife
Volume8
DOIs
StatePublished - Feb 8 2019

Fingerprint

Long Noncoding RNA
Premature Aging
Aging of materials
Physiology
Phenotype
Untranslated RNA
RNA-Binding Proteins
Tissue homeostasis
Genomic Instability
Mitosis
Homeostasis
RNA
Messenger RNA
Animals
Genes
Tissue
Proteins

Keywords

  • aging
  • chromosomes
  • gene expression
  • genetics
  • genomic stability
  • genomics
  • human
  • long noncoding RNA
  • mitochondria
  • mouse
  • Norad
  • PUMILIO

ASJC Scopus subject areas

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

Cite this

Kopp, F., Elguindy, M. M., Yalvac, M. E., Zhang, H., Chen, B., Gillett, F. A., ... Mendell, J. T. (2019). PUMILIO hyperactivity drives premature aging of Norad-deficient mice. eLife, 8. https://doi.org/10.7554/eLife.42650

PUMILIO hyperactivity drives premature aging of Norad-deficient mice. / Kopp, Florian; Elguindy, Mahmoud M.; Yalvac, Mehmet E.; Zhang, He; Chen, Beibei; Gillett, Frank A.; Lee, Sungyul; Sivakumar, Sushama; Yu, Hongtao; Xie, Yang; Mishra, Prashant; Sahenk, Zarife; Mendell, Joshua T.

In: eLife, Vol. 8, 08.02.2019.

Research output: Contribution to journalArticle

Kopp, F, Elguindy, MM, Yalvac, ME, Zhang, H, Chen, B, Gillett, FA, Lee, S, Sivakumar, S, Yu, H, Xie, Y, Mishra, P, Sahenk, Z & Mendell, JT 2019, 'PUMILIO hyperactivity drives premature aging of Norad-deficient mice', eLife, vol. 8. https://doi.org/10.7554/eLife.42650
Kopp F, Elguindy MM, Yalvac ME, Zhang H, Chen B, Gillett FA et al. PUMILIO hyperactivity drives premature aging of Norad-deficient mice. eLife. 2019 Feb 8;8. https://doi.org/10.7554/eLife.42650
Kopp, Florian ; Elguindy, Mahmoud M. ; Yalvac, Mehmet E. ; Zhang, He ; Chen, Beibei ; Gillett, Frank A. ; Lee, Sungyul ; Sivakumar, Sushama ; Yu, Hongtao ; Xie, Yang ; Mishra, Prashant ; Sahenk, Zarife ; Mendell, Joshua T. / PUMILIO hyperactivity drives premature aging of Norad-deficient mice. In: eLife. 2019 ; Vol. 8.
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