Integrator restrains paraspeckles assembly by promoting isoform switching of the lncRNA <i>NEAT1</i>

Abstract

RNA 3' end processing provides a source of transcriptome diversification which affects various (patho)-physiological processes. A prime example is the transcript isoform switch that leads to the read-through expression of the long non-coding RNA <i>NEAT1_2</i>, at the expense of the shorter polyadenylated transcript <i>NEAT1_1</i>. <i>NEAT1_2</i> is required for assembly of paraspeckles (PS), nuclear bodies that protect cancer cells from oncogene-induced replication stress and chemotherapy. Searching for proteins that modulate this event, we identified factors involved in the 3' end processing of polyadenylated RNA and components of the Integrator complex. Perturbation experiments established that, by promoting the cleavage of <i>NEAT1_2</i>, Integrator forces <i>NEAT1_2</i> to <i>NEAT1_1</i> isoform switching and, thereby, restrains PS assembly. Consistently, low levels of Integrator subunits correlated with poorer prognosis of cancer patients exposed to chemotherapeutics. Our study establishes that Integrator regulates PS biogenesis and a link between Integrator, cancer biology, and chemosensitivity, which may be exploited therapeutically.