BRCA1 exon 11 a model of long exon splicing regulation

Abstract

BRCA1 exon 11 is one of the biggest human exons, spanning 3426 bases. This gene is potentially involved in DNA repair as well as cell growth and cell cycle control. Exon 11 is regulated at the splicing level producing three main different combinations of BRCA1 mature transcripts; one including the whole of exon 11 (full isoform), one skipping the entire exon (D11 isoform), and one including only 117 base pairs of exon 11 (D11q isoform). Using minigene and deletion analyses, we have previously described important splicing regulatory sequences located at the beginning of this exon (5' end). We have now found additional important sequences located at its 3' end. In particular, we describe the presence of a strong splicing enhancer adjacent to the downstream 5' splice site, which minimizes competition from an upstream 5' splice site and so ensures long exon inclusion. Analyses of the proteins binding these RNA sequences have revealed that Tra2beta and hnRNP L are involved in the regulation of BRCA1 exon 11 by influencing the recognition of donor sites. Interestingly, BRCA1 exon 11 carrying deletion of the regulatory sequences bound by these factors also showed unexpected responses to up- or downregulation of these regulatory proteins, suggesting that they can also bind elsewhere in this large exon and elicit different effects on its recognition. The identification of sequences and proteins relevant for the regulation of BRCA1 exon 11 now provides better knowledge on how this exon is recognized and may represent an important step toward understanding how large exons are regulated.

Germline mutations of BRCA1 gene exon 11 are not associated with platinum response neither with survival advantage in patients with primary ovarian cancer: understanding the clinical importance of one of the biggest human exons. A study of the Tumor Bank Ovarian Cancer (TOC) Consortium

“…The present study aimed to assess in a large cohort of EOC patients the clinical impact of germline mutations in BRCA1 gene exon 11, one of the biggest human exons covering 60 % of BRCA1 gene sequence (more than 3 kb) [15,16]. The study showed that in a large cohort of primary OC patients tested for BRCA1 exon 11 mutations, no difference between mutated and wild-type patients were found in terms of optimal debulking rate, platinum response, and survival.…”

“…Exon 11 is the largest exon of the BRCA1 gene sequence and one of the largest exons of the human genome (3426 bases). It comprises 60 % of coding region for the BRCA1 protein [15,16].…”

The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

“…The BRCA1-Δ11q isoform derives from use of an alternative exon 11 splice donor site, resulting in the exclusion of most exon 11 nucleotides (c.788-4096) (Supplementary Fig. S1) (27, 28). In human cells and tissues, the BRCA1- Δ11q isoform expression is more readily detectable than the BRCA1-Δ11 isoform (26, 29, 30).…”

Transformer 2β homolog (Drosophila) (TRA2B) Regulates Protein Kinase C δI (PKCδI) Splice Variant Expression during 3T3L1 Preadipocyte Cell Cycle

“…Regulation of alternative splicing by TRA2B is shown in several systems including LIPN1 in liver (28), splicing of myosin phosphatase targeting subunit 1 in smooth muscle (29), splicing of Tau in neurons (30) and BRCA1 gene (31). TRA2B is also shown to be involved in mouse embryogenesis and spermatogenesis as well as in meiosis in male germ cells (32).…”