Structural determinants of BRCA1 translational regulation

The BRCA1 gene is involved in sporadic breast and ovarian cancer mainly through reduced expression. BRCA1 mRNAs containing different leader sequences show different patterns of expression. In a normal mammary gland mRNA with a shorter leader sequence, 5'-UTRa is expressed only, whereas in breast cancer tissue mRNA with a longer leader, 5'-UTRb is expressed also. We show that the translation efficiency of transcripts containing 5'-UTRb is 10 times lower than those containing 5'-UTRa. The structures of 5'-UTRa and 5'-UTRb were determined by chemical and enzymatic probing aided by a new method developed for monitoring the number of co-existing stable conformers. Specific factors responsible for reduced translation of mRNA containing 5'-UTRb were determined using a variety of transcripts with mutations in the leader sequence. These factors include a stable secondary structure formed by truncated Alu element and upstream AUG codons. The novel mechanism by which BRCA1 may be involved in sporadic breast and ovarian cancer is proposed. It is based on the expression patterns of BRCA1 mRNAs and differences in their translatability. According to this mechanism the deregulation of the BRCA1 transcription in cancer, resulting in a higher proportion of translationally inhibited transcripts containing 5'-UTRb, contributes to the decrease in the BRCA1 protein observed in sporadic breast and ovarian cancers.