The SINEB1 element in the long non-coding RNA Malat1 is necessary for TDP-43 proteostasis.

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 Res

journal_title

Nucleic acids research

authors

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,Ro

doi

10.1093/nar/gkz1176

subject

Has Abstract

pub_date

2020-03-18 00:00:00

pages

2621-2642

issue

5

eissn

0305-1048

issn

1362-4962

pii

5682909

journal_volume

48

pub_type

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