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

2018-08Journal article Open access
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dc.contributor.authorBraun, Simon
dc.contributor.authorEnculescu, Mihaela
dc.contributor.authorSetty, Samarth T.
dc.contributor.authorCortes-Lopez, Mariela
dc.contributor.authorAlmeida, Bernardo
dc.contributor.authorSutandy, F. X. Reymond
dc.contributor.authorSchulz, Laura
dc.contributor.authorBusch, Anke
dc.contributor.authorSeiler, Markus
dc.contributor.authorEbersberger, Stefanie
dc.contributor.authorBarbosa-Morais, Nuno L.
dc.contributor.authorLegewie, Stefan
dc.contributor.authorKonig, Julian
dc.contributor.authorZarnack, Kathi
dc.date.accessioned2018-12-07T14:52:38Z
dc.date.available2018-12-07T14:52:38Z
dc.date.issued2018-08
dc.description.abstractMutations 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 Delta 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.
dc.description.sponsorshipInstitute of Molecular Biology Core Facilities; DFG [ZA 881/2-1, KO 4566/4-1, LE 3473/2-1]; LOEWE program Ubiquitin Networks (Ub-Net) of the State of Hesse (Germany); Deutsche Forschungsgemeinschaft [SFB902 B13]; EMBO [3057]; Fundacao para a Ciencia e a Tecnologia, Portugal (FCT Investigator Starting Grant) [IF/00595/2014]; German Federal Ministry of Research (BMBF; e:bio junior group program) [FKZ: 0316196]; Boehringer Ingelheim Foundation; [INST 47/870-1 FUGG]
dc.identifier.doi10.1038/s41467-018-05748-7
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/10400.1/11139
dc.language.isoeng
dc.peerreviewedyes
dc.publisherNature Publishing Group
dc.relationRNA in disease
dc.subjectReceptor Tyrosine Kinase
dc.subjectMacrophage-Stimulating Protein
dc.subjectRna-Binding Proteins
dc.subjectSynonymous Mutations
dc.subjectSelection Pressure
dc.subjectG-Quadruplex
dc.subjectTranscription
dc.subjectExpression
dc.subjectNetworks
dc.subjectGenome
dc.titleDecoding a cancer-relevant splicing decision in the RON proto-oncogene using high-throughput mutagenesis
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleRNA in disease
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/857119/EU
oaire.citation.startPage3315
oaire.citation.titleNature Communications
oaire.citation.volume9
oaire.fundingStreamH2020
person.familyNameAlmeida
person.givenNameBernardo
person.identifier.orcid0000-0002-6084-6775
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameEuropean Commission
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublicationa20b550d-d54a-46ae-9e17-3eb5fa5409cc
relation.isAuthorOfPublication.latestForDiscoverya20b550d-d54a-46ae-9e17-3eb5fa5409cc
relation.isProjectOfPublication0888f06d-3d00-4d61-8a9a-dd1663f3d2a5
relation.isProjectOfPublication.latestForDiscovery0888f06d-3d00-4d61-8a9a-dd1663f3d2a5

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