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

Nucleic Acids Res. 2020 Mar 18;48(5):2621-2642. doi: 10.1093/nar/gkz1176.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Line
  • Cytoplasm / metabolism
  • DNA Damage
  • DNA-Binding Proteins / metabolism*
  • Endoplasmic Reticulum Stress
  • Enzyme Activation
  • Gene Dosage
  • Heterogeneous-Nuclear Ribonucleoprotein K / metabolism
  • Humans
  • Mitosis
  • Models, Biological
  • Protein Transport
  • Proteostasis / genetics*
  • RNA, Long Noncoding / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sequence Deletion / genetics
  • Short Interspersed Nucleotide Elements / genetics*
  • eIF-2 Kinase


  • DNA-Binding Proteins
  • Heterogeneous-Nuclear Ribonucleoprotein K
  • MALAT1 long non-coding RNA, human
  • RNA, Long Noncoding
  • RNA, Messenger
  • TARDBP protein, human
  • eIF-2 Kinase