The SINEB1 Element in the Long Non-Coding RNA Malat1 is Necessary for TDP-43 Proteostasis

Transposable elements (TEs) are prevalent in the mammalian genome and 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 in contrast to wildtype Malat1 is frequently translocated to the cytoplasm. SINE-deleted cells exhibit altered cell cycle kinetics with delayed S and G2/M and increased mitotic catastrophe. Molecular analyses confirmed activation of the unfolded protein response as well as increased DNA damage and apoptosis caused by dysregulation of TDP-43 localization and formation of cytotoxic aggregates. TDP-43 cytoplasmic localization, likely due to direct binding to Malat1, resulted in the depletion of nuclear TDP-43 and redistribution of TDP- 43 binding to mRNAs encoding mitotic and nuclear-cytoplasmic regulators. These results highlight the significance of TEs in proteostasis.