Abstract:
: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.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Nguyen TM,Kabotyanski EB,Reineke LC,Shao J,Xiong F,Lee JH,Dubrulle J,Johnson H,Stossi F,Tsoi PS,Choi KJ,Ellis AG,Zhao N,Cao J,Adewunmi O,Ferreon JC,Ferreon ACM,Neilson JR,Mancini MA,Chen X,Kim J,Ma L,Li W,Rodoi
10.1093/nar/gkz1176subject
Has Abstractpub_date
2020-03-18 00:00:00pages
2621-2642issue
5eissn
0305-1048issn
1362-4962pii
5682909journal_volume
48pub_type
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