Identification and functional analysis of novel BRCA1 transcripts, including mouse Brca1-Iris and human pseudo-BRCA1

Recent characterization of the mammalian transcriptome has confirmed its predicted complexity, with many loci encoding multiple splice variants and pseudogenes. The breast cancer susceptibility gene BRCA1 is a tumour suppressor gene that produces multiple functional transcripts. For example, BRCA1-IRIS is a splice variant of BRCA1, which encodes a protein that is functionally distinct from BRCA1. Here we describe the identification of ten novel Brca1 splice variants including Brca1-Iris, the mouse orthologue of human BRCA1-IRIS. We show that Brca1-Iris is differentially expressed during mammary epithelial differentiation and regulates survival of mammary epithelial cells. Another transcript, Brca1-Delta22, expressed in both mouse and human cells, was found to be defective in transcriptional activation capacity. Finally, we show that the human BRCA1 pseudogene produces a spliced pseudoBRCA1 transcript. The identification of these transcripts has implications for the understanding of the role of BRCA1 in biology and disease and for the interpretation of mouse knockout models.