Journal
NUCLEIC ACIDS RESEARCH
Volume 45, Issue 11, Pages 6761-6774Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkx225
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Funding
- UK Medical Research Council [U117574558, MC_PC_1 3051, FC001178]
- Biotechnology and Biological Sciences Research Council [BB/M001199/1, BB/M007103/1]
- National Medical Research Council [NMRC/CBRG/0028/2013]
- University College London
- Francis Crick Institute
- Cancer Research UK [FC001178]
- Wellcome trust [FC001178]
- BBSRC-UCL
- BBSRC [BB/M001199/1, BB/M007103/1] Funding Source: UKRI
- MRC [MC_PC_13051, MC_U117574558, MC_U117533887] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/M001199/1, BB/M007103/1] Funding Source: researchfish
- Medical Research Council [MC_U117574558, MC_PC_13051, MC_U117533887] Funding Source: researchfish
- The Francis Crick Institute [10029, 10178] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10015] Funding Source: researchfish
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RBM10 is an RNA-binding protein that plays an essential role in development and is frequentlymutated in the context of human disease. RBM10 recognizes a diverse set of RNA motifs in introns and exons and regulates alternative splicing. However, the molecular mechanisms underlying this seemingly relaxed sequence specificity are not understood and functional studies have focused on 3' intronic sites only. Here, we dissect the RNA code recognized by RBM10 and relate it to the splicing regulatory function of this protein. We show that a two-domain RRM1-ZnF unit recognizes a GGA-centered motif enriched in RBM10 exonic sites with high affinity and specificity and test that the interaction with these exonic sequences promotes exon skipping. Importantly, a second RRM domain (RRM2) of RBM10 recognizes a C-rich sequence, which explains its known interactionwith the intronic 3' site of NUMB exon 9 contributing to regulation of the Notch pathway in cancer. Together, these findings explain RBM10's broad RNA specificity and suggest that RBM10 functions as a splicing regulator using two RNA-binding units with different specificities to promote exon skipping.
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