title: BRCA1 EXON 11, a CERES (composite regulatory element of splicing) element involved in splice regulation.
abstract: Unclassified variants (UV) of BRCA1 can affect normal pre-mRNA splicing. Here, we investigate the UV c.693G>A, a "silent" change in BRCA1 exon 11, which we have found induces aberrant splicing in patient carriers and in vitro. Using a minigene assay, we show that the UV c.693G>A has a strong effect on the splicing isoform ratio of BRCA1. Systematic site-directed mutagenesis of the area surrounding the nucleotide position c.693G>A induced variable changes in the level of exon 11 inclusion/exclusion in the mRNA, pointing to the presence of a complex regulatory element with overlapping enhancer and silencer functions. Accordingly, protein binding analysis in the region detected several splicing regulatory factors involved, including SRSF1, SRSF6 and SRSF9, suggesting that this sequence represents a composite regulatory element of splicing (CERES).
authors: Human Development and Health, University of Southampton, Southampton SO16 6YD, UK. ct4e10@soton.ac.uk.
authors: Claudia
authors: C
authors: Tammaro
authors: Human Development and Health, University of Southampton, Southampton SO16 6YD, UK. m.raponi@soton.ac.uk.
authors: Michela
authors: M
authors: Raponi
authors: Human Development and Health, University of Southampton, Southampton SO16 6YD, UK. d.i.wilson@soton.ac.uk.
authors: David I
authors: DI
authors: Wilson
authors: Human Development and Health, University of Southampton, Southampton SO16 6YD, UK. d.baralle@soton.ac.uk.
authors: Diana
authors: D
authors: Baralle
mesh_terms: D017398:Alternative Splicing; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D005091:Exons; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors
chemical_list: D019313:BRCA1 Protein; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors