Emerging roles of BRCA1 alternative splicing

Abstract

Germline mutations of the BRCA1 gene predispose individuals mainly to the development of breast and/or ovarian cancer. However, the exact function of the gene is still unclear, although the encoded proteins are involved in various cellular processes, including transcriptional regulation and DNA repair pathways. Several BRCA1 splice variants are found in different tissues, but in spite of intense investigations, their regulation and possible functions are poorly understood at the moment. This review summarises current knowledge on the roles of these splice variants and the mechanisms responsible for their formation. Because alternative splicing is now widely accepted as an important source of genetic diversity, elucidating the functions of the BRCA1 splice variants would help in the understanding of the exact role(s) of this tumour suppressor. This should help to resolve the current paradox that, despite its seemingly vital cellular functions, mutations of this gene are associated with tissue specific tumour formation predominantly in the breast and the ovary.

Figure 1

Structures of the BRCA1 mRNA variants that keep the original open reading frame and hence are capable of encoding functional protein species (see table 1 ▶). Numbers correspond to different exons, and the missing exons are shown by connecting lines in each variant. Exons are not drawn to scale, although as indicated exon 11 is much longer than the others. Note that exons 1a and 1b are shown with the full length mRNA species only, because it is currently unknown whether the splicing profiles of the further 3′ exons are different for these two mutually exclusive exons.