The SINEB1 element in the long non-coding RNA Malat1 is necessary for TDP-43 proteostasis
| Autor: | Kyoung-Jae Choi, Xi Chen, Josephine C. Ferreon, Phoebe S. Tsoi, Jin Cao, Michael A. Mancini, Jongchan Kim, Oluwatoyosi Adewunmi, Feng Xiong, Jiaofang Shao, Fabio Stossi, Elena B. Kabotyanski, Na Zhao, Alexander G. Ellis, Jeffrey M. Rosen, Lucas C. Reineke, Joel R. Neilson, Joo-Hyung Lee, Wenbo Li, Julien Dubrulle, Allan Chris M. Ferreon, Hannah L. Johnson, Tuan M. Nguyen, Li Ma |
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| Rok vydání: | 2019 |
| Předmět: |
Cytoplasm
Gene Dosage Mitosis Apoptosis Biology Models Biological behavioral disciplines and activities Cell Line Heterogeneous-Nuclear Ribonucleoprotein K eIF-2 Kinase 03 medical and health sciences 0302 clinical medicine RNA and RNA-protein complexes Genetics Humans RNA Messenger Binding site Sequence Deletion Short Interspersed Nucleotide Elements 030304 developmental biology 0303 health sciences RNA Endoplasmic Reticulum Stress Long non-coding RNA Transport protein Cell biology DNA-Binding Proteins Enzyme Activation Protein Transport Proteostasis Unfolded protein response RNA Long Noncoding 030217 neurology & neurosurgery DNA Damage |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | Transposable elements (TEs) comprise a large proportion of long non-coding RNAs (lncRNAs). Here, we employed CRISPR to delete a short interspersed nuclear element (SINE) in Malat1, a cancer-associated lncRNA, to investigate its significance in cellular physiology. We show that Malat1 with a SINE deletion forms diffuse nuclear speckles and is frequently translocated to the cytoplasm. SINE-deleted cells exhibit an activated unfolded protein response and PKR and markedly increased DNA damage and apoptosis caused by dysregulation of TDP-43 localization and formation of cytotoxic inclusions. TDP-43 binds stronger to Malat1 without the SINE and is likely ‘hijacked’ by cytoplasmic Malat1 to the cytoplasm, resulting in the depletion of nuclear TDP-43 and redistribution of TDP-43 binding to repetitive element transcripts and mRNAs encoding mitotic and nuclear-cytoplasmic regulators. The SINE promotes Malat1 nuclear retention by facilitating Malat1 binding to HNRNPK, a protein that drives RNA nuclear retention, potentially through direct interactions of the SINE with KHDRBS1 and TRA2A, which bind to HNRNPK. Losing these RNA–protein interactions due to the SINE deletion likely creates more available TDP-43 binding sites on Malat1 and subsequent TDP-43 aggregation. These results highlight the significance of lncRNA TEs in TDP-43 proteostasis with potential implications in both cancer and neurodegenerative diseases. |
| Databáze: | OpenAIRE |
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