Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 15, Issue 7, Pages 13045-13059Publisher
MDPI AG
DOI: 10.3390/ijms150713045
Keywords
BRCA1; splicing; unclassified variant; alternative splicing; minigene; exon 11
Funding
- Higher Education Funding Council, UK
- Cancer Research UK
- EURASNET (European alternative splicing network of excellence)
- ICGEB (International Centre for Genetic Engineering and Biotechnology)
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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).
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