Discovery of Achilles heel in the cancer-associated RBM39 gene

September 4, 2023

NOMIS researcher Marc-David Ruepp and colleagues have discovered a mechanism of RBM39 autoregulation, providing a solid basis to design alternative anti-cancer therapies. Their findings were published in Nature.

RBM39 is an RNA-binding protein found in all cell types throughout the body and regulates the alternative splicing of precursor messenger RNAs (pre-mRNAs) following their production from genomic DNA. In doing so, RBM39 contributes to the decision which mature mRNA isoforms are ultimately made from any gene, which has far-reaching consequences because such mRNA isoforms may differ in their stability and the type of protein they encode.

Notably, RBM39 is upregulated in several types of cancer including acute myeloid leukemia and is required for the survival of cancer cells, which makes RBM39 a promising therapeutic target.

Marc-David Ruepp

In an interdisciplinary project, the Allain, Ruepp and Campagne labs aimed to better understand the molecular details of how RBM39 regulates alternative splicing. Hereto, they first solved the solution structures of both RNA-binding domains of RBM39 in their RNA-bound state using NMR spectroscopy. Combined, these structures provide atomic resolution insight into how RBM39 specifically selects short RNA motifs, which are scattered along the comparatively vast pre-mRNAs. Using an unbiased high-throughput approach, they identified thousands of alternative splicing events that are regulated by RBM39. Among those, they discovered an alternative splicing event in the pre-mRNA encoding the RBM39 protein itself, favoring the production of an mRNA isoform that is rapidly degraded in the cell. This mechanism forms the basis of a negative feedback loop that helps to balance RBM39 levels in healthy cells.

Given that reducing RBM39 levels is beneficial in acute myeloid leukemia, this newly discovered mechanism of RBM39 autoregulation could be leveraged for targeted therapeutic intervention.

Read the Nature publication: Molecular basis of RNA-binding and autoregulation by the cancer-associated splicing factor RBM39