PUMILIO hyperactivity drives premature aging of Norad-deficient mice
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 mitochond...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/42650 |
| _version_ | 1828221829285675008 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Florian Kopp |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T16:46:44Z |
| format | Article |
| id | doaj.art-11ac600402c64f12aeffc40cfa19a3d5 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:46:44Z |
| publishDate | 2019-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-11ac600402c64f12aeffc40cfa19a3d52022-12-22T03:24:33ZengeLife Sciences Publications LtdeLife2050-084X2019-02-01810.7554/eLife.42650PUMILIO hyperactivity drives premature aging of Norad-deficient miceFlorian Kopp0https://orcid.org/0000-0001-9952-635XMahmoud M Elguindy1https://orcid.org/0000-0001-9151-1751Mehmet E Yalvac2He Zhang3Beibei Chen4Frank A Gillett5Sungyul Lee6https://orcid.org/0000-0003-3207-1199Sushama Sivakumar7https://orcid.org/0000-0001-7877-4821Hongtao Yu8https://orcid.org/0000-0002-8861-049XYang Xie9Prashant Mishra10Zarife Sahenk11Joshua T Mendell12https://orcid.org/0000-0001-8479-2284Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United StatesCenter for Gene Therapy, Nationwide Children's Hospital, Columbus, United States; Department of Neurology, The Ohio State University, Columbus, United StatesQuantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, United States; Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, United StatesQuantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, United States; Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United StatesQuantitative 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 StatesChildren's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, United StatesCenter 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 StatesDepartment 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 StatesAlthough 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.https://elifesciences.org/articles/42650long noncoding RNAagingNoradPUMILIOgenomic stabilitymitochondria |
| spellingShingle | 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 PUMILIO hyperactivity drives premature aging of Norad-deficient mice eLife long noncoding RNA aging Norad PUMILIO genomic stability mitochondria |
| title | PUMILIO hyperactivity drives premature aging of Norad-deficient mice |
| title_full | PUMILIO hyperactivity drives premature aging of Norad-deficient mice |
| title_fullStr | PUMILIO hyperactivity drives premature aging of Norad-deficient mice |
| title_full_unstemmed | PUMILIO hyperactivity drives premature aging of Norad-deficient mice |
| title_short | PUMILIO hyperactivity drives premature aging of Norad-deficient mice |
| title_sort | pumilio hyperactivity drives premature aging of norad deficient mice |
| topic | long noncoding RNA aging Norad PUMILIO genomic stability mitochondria |
| url | https://elifesciences.org/articles/42650 |
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