University of Cambridge > > Babraham Seminar > Decoding a cancer-relevant splicing decision in the RON proto-oncogene using high-throughput mutagenesis

Decoding a cancer-relevant splicing decision in the RON proto-oncogene using high-throughput mutagenesis

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Mutations causing aberrant splicing are frequently implicated in human diseases including cancer. Splicing requires tight control of trans-acting factors that recognise cis-regulatory elements in the RNA sequence. However, the position and function of most cis-regulatory elements remain unknown, hindering the interpretation of disease-associated mutations and resulting splicing changes. We recently established a high-throughput screen of randomly mutated minigenes to decode the cis-regulatory landscape of selected splicing decisions. As a prototype example, we tested the cancer-relevant alternative exon 11 in the proto-oncogene MST1R (RON). Skipping of RON exon 11 results in the pathological isoform RON ∆165 results that promotes tumour invasiveness and is frequently upregulated in solid tumours. Mathematical modelling of splicing kinetics enables us to identify more than 1,000 mutations affecting RON exon 11 skipping. Importantly, the effects correlate with RON alternative splicing in cancer patients bearing the same mutations. Moreover, we highlight heterogeneous nuclear ribonucleoprotein H (HNRNPH) as a key regulator of RON splicing in healthy tissues and cancer. Using iCLIP and synergy analysis, we pinpoint the functionally most relevant HNRNPH binding sites and demonstrate how cooperative HNRNPH binding facilitates a splicing switch of RON exon 11. Our results thereby offer insights into splicing regulation and the impact of mutations on alternative splicing in cancer.

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