Identification of BRCA1-IRIS, a BRCA1 locus product

Breast cancer is the most common malignancy among women, and mutations in the BRCA genes produce increased susceptibility to these malignancies in certain families. Here we identify BRCA1-IRIS as a 1,399-amino-acid BRCA1 gene product encoded by an uninterrupted open reading frame that extends from codon 1 of the known BRCA1 open reading frame to a termination point 34 triplets into intron 11. Unlike full-length BRCA1 (p220), BRCA1-IRIS is exclusively chromatin-associated, fails to interact with BARD1 in vivo or in vitro and exhibits unique nuclear immunostaining. Unlike BRCA1FL (or p220), BRCA1-IRIS also co-immunoprecipitated with DNA-replication-licensing proteins and with known replication initiation sites. Suppression of BRCA1-IRIS expression hindered the normal departure of geminin from pre-replication complexes, and depressed the rate of cellular DNA replication and possibly initiation-related synthesis. In contrast, BRCA1-IRIS overexpression stimulated DNA replication. These data imply that endogenous BRCA1-IRIS positively influences the DNA replication initiation machinery.