LOCALIZATION OF BRCA1 AND A SPLICE VARIANT IDENTIFIES THE NUCLEAR-LOCALIZATION SIGNAL

Inherited mutations in BRCA1 confer susceptibility to breast and ovari an neoplasms. However, the function of BRCA1 and the role of BRCA1 in noninherited cancer remain unknown. Characterization of alternately sp liced forms of BRCA1 may identify functional regions; thus, we constru cted expression vectors of BRCA1 and a splice variant lacking exon II, designated BRCA1 Delta 672-4095. Immunofluorescence studies indicate nuclear localization of BRCA1 but cytoplasmic localization of BRCA1 De lta 672-4095. Two putative nuclear localization signals (designated NL S1 and NLS2) were identified in exon II; immunofluorescence studies in dicate that only NLS1 is required for nuclear localization RNA analysi s indicates the expression of multiple, tissue-specific forms of BRCA1 RNAs; protein analysis with multiple antibodies suggests that at leas t three BRCA1 isoforms are expressed, including those lacking exon 11, The results suggest that BRCA1 is a nuclear protein and raise the pos sibility that splicing is one form of regulation of BRCA1 function by alteration of the subcellular localization of expressed proteins.