Transcription within the nucleus is physically separated from translation in the cytoplasm by the nuclear envelope, which encapsulates the genome. This necessitates the continuous transport of RNA through nuclear pores, defined as mRNA export. Facilitated by mRNA export complexes TREX and TREX-2, intranuclear transit of Poly(A)+ mRNA is proposed to occur in a diffusive manner through the interchromatin space.
In addition to their therapeutic potential, small molecule inhibitors have become invaluable tools for molecularly characterising diverse biological pathways leading to major scientific advances. Using a high-throughput phenotypic screening approach, we have identified compounds which inhibit mRNA export. Specifically, we have identified one class of compounds, named “compound C”, which selectively perturbs mRNA export of TREX transcripts. Strikingly, cells treated with compound C show accumulation of mRNA within the interchromatin space in large foci devoid of nuclear speckle proteins. Proteomic analysis has shown TREX interacts with the actin polymerisation machinery and chromatin remodelling complex, BAF, and this interaction is disrupted by Compound C.
Live- and fixed-cell imaging experiments demonstrate nuclear actin and actin polymerisation are required for normal mRNA intranuclear transport and export. Future work will focus on elucidating how the interaction between the mRNA export machinery, nuclear actin and BAF complex regulates intranuclear mRNA transit.