In a "Nature Communications" paper, the Allain (ETH Zurich), Campagne (University of Bordeaux, France) and Ruepp (King’s College London, UK) groups report that the RBM39 protein autoregulates itself through regulation of a poison exon. Altering this exon’s splicing could be a novel approach for cancer treatment.
The RNA binding protein RBM39 is important for the survival of several types of cancer cells. Molecules acting as a glue between RBM39 and DCAF15, which in turn forms complexes with ubiquitin ligases, lead to RBM39’s degradation. This approach has shown treatment potential in several cancer models. However, this type of treatment depends on sufficient levels of DCAF15 to lower RBM39 levels for therapeutic benefit.
The researchers assessed RBM39’s influence on the transcriptome and alternative splicing by high throughput sequencing and in follow up experiments investigated the contributions of each of the four protein domains to its function, assessed the RNA binding specificity of two domains and solved the corresponding complex structures by Nuclear Magnetic Resonance. This led them to propose a molecular model of how RBM39 influences splicing through recruitment of spliceosome components to respective target pre-mRNAs.
Intriguingly, RBM39 binds to its own pre-mRNA and promotes inclusion of a so-called poison exon into the mature mRNA. Poison exons contain premature termination codons leading to the degradation of the containing mRNA by nonsense-mediated decay (NMD). Increasing the inclusion of this poison exon through an antisense oligonucleotide or a small molecule altering the splicing, could be an alternative way to decrease RBM39 levels in cancer cells for therapeutic benefit independent of the levels of the adaptor protein.