BRCA1 Exon 11, a CERES (Composite Regulatory Element of Splicing) Element Involved in Splice Regulation

International Journal of Molecular Sciences

Claudia Tammaro¹  Michela Raponi¹  David I. Wilson¹ 

[1] Human Development and Health, University of Southampton, Southampton SO16 6YD, UK;

关键词: BRCA1;    splicing;    unclassified variant;    alternative splicing;    minigene;    exon11;   

DOI  :  10.3390/ijms150713045

来源: mdpi

【 摘 要 】

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).

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.