DND1 maintains germline stem cells via recruitment of the CCR4–NOT complex to target mRNAs
| Autor: | Aitor Garzia, Misaki Yamaji, Thomas Tuschl, Hannah L. McFarland, Cindy Meyer, Markus Hafner, Miki Jishage, Sudhir Manickavel, Pavel Morozov, Robert G. Roeder, Evan Der, Masashi Yamaji, Hemant Suryawanshi |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
Pluripotent Stem Cells 0301 basic medicine endocrine system Transcription Genetic MRNA destabilization RNA Stability Cellular differentiation Apoptosis Biology Article Germline Mice 03 medical and health sciences Ribonucleases Transforming Growth Factor beta medicine CCR4-NOT complex Animals Humans Gene silencing Gene Silencing RNA Messenger Nucleotide Motifs 3' Untranslated Regions Inflammation Genetics Binding Sites Multidisciplinary Base Sequence Three prime untranslated region Gene Expression Profiling Stem Cells Cell Differentiation Spermatogonia Neoplasm Proteins Cell biology 030104 developmental biology medicine.anatomical_structure Multiprotein Complexes Stem cell Germ cell Protein Binding Signal Transduction Transcription Factors |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature21690 |
| Popis: | The vertebrate-conserved RNA-binding protein (RBP) DND1 is required for survival of primordial germ cells (PGCs), as well as germ cell tumour (TGCT) suppression in mice1–5. Here we report that DND1 binds a UU[A/U] trinucleotide motif predominantly in messenger RNA (mRNA) 3′ untranslated regions (UTRs), and destabilizes target mRNAs through direct recruitment of the CCR4-NOT deadenylase (CCR4) complex. Transcriptomic analysis revealed that the extent of suppression is dependent on the number of DND1 binding sites. The DND1-dependent mRNA destabilization is required for survival of murine PGCs and spermatogonial stem cells (SSCs) by suppressing apoptosis. The target RNA spectrum includes positive regulators of apoptosis, inflammation, and modulators of signalling pathways regulating stem cell pluripotency including the TGF-β super family, all of which are aberrantly elevated in Dnd1-deficient PGCs. We propose that the induction of the posttranscriptional suppressor DND1 synergizes with concurrent transcriptional changes to sharpen developmental transitions during cellular differentiation and maintenance of the germline. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink