Esfahani MS, Lee LJ, Jeon YJ, Flynn RA, Stehr H, Hui AB, Ishisoko N, Kildebeck E, Newman AM, Bratman SV, Porteus MH, Chang HY, Alizadeh AA, Diehn M. Functional significance of U2AF1 S34F mutations in lung adenocarcinomas. Nat Commun. 2019 12 13; 10(1):5712.

Citation

Esfahani MS, Lee LJ, Jeon YJ, Flynn RA, Stehr H, Hui AB, Ishisoko N, Kildebeck E, Newman AM, Bratman SV, Porteus MH, Chang HY, Alizadeh AA, Diehn M. 2019. Functional significance of U2AF1 S34F mutations in lung adenocarcinomas. Nature communications. 10(1):5712. Pubmed: 31836708 DOI:10.1038/s41467-019-13392-y

Abstract

The functional role of U2AF1 mutations in lung adenocarcinomas (LUADs) remains incompletely understood. Here, we report a significant co-occurrence of U2AF1 S34F mutations with ROS1 translocations in LUADs. To characterize this interaction, we profiled effects of S34F on the transcriptome-wide distribution of RNA binding and alternative splicing in cells harboring the ROS1 translocation. Compared to its wild-type counterpart, U2AF1 S34F preferentially binds and modulates splicing of introns containing CAG trinucleotides at their 3' splice junctions. The presence of S34F caused a shift in cross-linking at 3' splice sites, which was significantly associated with alternative splicing of skipped exons. U2AF1 S34F induced expression of genes involved in the epithelial-mesenchymal transition (EMT) and increased tumor cell invasion. Finally, S34F increased splicing of the long over the short SLC34A2-ROS1 isoform, which was also associated with enhanced invasiveness. Taken together, our results suggest a mechanistic interaction between mutant U2AF1 and ROS1 in LUAD.

Related Faculty

Ryan Flynn, M.D., Ph.D.

Flynn Lab

Ryan Flynn’s laboratory is focused on the exploration and discovery of how biopolymers like RNA and glycans work together to control cellular processes in the context of human disease.