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SUMMARY:Decoding a cancer-relevant splicing decision in the RON proto-onco
 gene using high-throughput mutagenesis - Dr Kathi Zarnack\; Buchmann Insti
 tute for Molecular Life Sciences 
DTSTART:20190305T133000Z
DTEND:20190305T143000Z
UID:TALK120877@talks.cam.ac.uk
CONTACT:Bobbie Claxton
DESCRIPTION:Mutations causing aberrant splicing are frequently implicated 
 in human diseases including cancer. Splicing requires tight control of tra
 ns-acting factors that recognise cis-regulatory elements in the RNA sequen
 ce. However\, the position and function of most cis-regulatory elements re
 main unknown\, hindering the interpretation of disease-associated mutation
 s and resulting splicing changes. We recently established a high-throughpu
 t screen of randomly mutated minigenes to decode the cis-regulatory landsc
 ape of selected splicing decisions. As a prototype example\, we tested the
  cancer-relevant alternative exon 11 in the proto-oncogene MST1R (RON). Sk
 ipping of RON exon 11 results in the pathological isoform RON∆165 result
 s that promotes tumour invasiveness and is frequently upregulated in solid
  tumours. Mathematical modelling of splicing kinetics enables us to identi
 fy more than 1\,000 mutations affecting RON exon 11 skipping. Importantly\
 , the effects correlate with RON alternative splicing in cancer patients b
 earing the same mutations. Moreover\, we highlight heterogeneous nuclear r
 ibonucleoprotein H (HNRNPH) as a key regulator of RON splicing in healthy 
 tissues and cancer. Using iCLIP and synergy analysis\, we pinpoint the fun
 ctionally most relevant HNRNPH binding sites and demonstrate how cooperati
 ve HNRNPH binding facilitates a splicing switch of RON exon 11. Our result
 s thereby offer insights into splicing regulation and the impact of mutati
 ons on alternative splicing in cancer.
LOCATION:Babraham - The Cambridge Building - The Kings Hedges Room
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