TY  - JOUR
A1  - Braun, Simon
A1  - Enculescu, Mihaela
A1  - Setty, Samarth T.
A1  - Cortés-López, Mariela
A1  - Pinto de Almeida, Bernardo
A1  - Sutandy, F. X. Reymond
A1  - Schulz, Laura
A1  - Busch, Anke
A1  - Seiler, Markus
A1  - Ebersberger, Stefanie
A1  - Barbosa-Morais, Nuno L.
A1  - Legewie, Stefan
A1  - König, Julian
A1  - Zarnack, Katharina
T1  - Decoding a cancer-relevant splicing decision in the RON proto-oncogene using high-throughput mutagenesis
T2  - Nature Communications
N2  - Mutations causing aberrant splicing are frequently implicated in human diseases including cancer. Here, we establish a high-throughput screen of randomly mutated minigenes to decode the cis-regulatory landscape that determines alternative splicing of exon 11 in the proto-oncogene MST1R (RON). Mathematical modelling of splicing kinetics enables us to identify more than 1000 mutations affecting RON exon 11 skipping, which corresponds to the pathological isoform RON∆165. 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.
KW  - Alternative splicing
KW  - Cancer genomics
KW  - Computational models
KW  - High-throughput screening
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/46476
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-464766
SN  - 2041-1723
N1  - Rights and permissions: Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
VL  - 9
IS  - 1, Art. 3315
SP  - 1
EP  - 18
PB  - Nature Publishing Group UK
CY  - [London]
ER  -