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Nucleic Acids Res ; 48(5): 2621-2642, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-31863590

RESUMO

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.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteostase/genética , RNA Longo não Codificante/genética , Elementos Nucleotídeos Curtos e Dispersos/genética , Apoptose , Linhagem Celular , Citoplasma/metabolismo , Dano ao DNA , Estresse do Retículo Endoplasmático , Ativação Enzimática , Dosagem de Genes , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , Humanos , Mitose , Modelos Biológicos , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Deleção de Sequência/genética , eIF-2 Quinase
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