Both human and mouse cells express an alternatively spliced variant of BRCA1, BRCA1-⌬11, which lacks exon 11 in its entirety, including putative nuclear localization signals. Consistent with this, BRCA1-⌬11 has been reported to reside in the cytoplasm, a localization that would ostensibly preclude it from playing a role in the nuclear processes in which its full-length counterpart has been implicated. Nevertheless, the finding that murine embryos bearing homozygous deletions of exon 11 survive longer than embryos that are homozygous for Brca1 null alleles suggests that exon 11-deleted isoforms may perform at least some of the functions of Brca1. We have analyzed both the full-length and the exon 11-deleted isoforms of the murine Brca1 protein.Our results demonstrate that full-length murine Brca1 is identical to human BRCA1 with respect to its cell cycle regulation, DNA damage-induced phosphorylation, nuclear localization, and association with Rad51. Surprisingly, we show that endogenous Brca1-⌬11 localizes to discrete nuclear foci indistinguishable from those found in wild-type cells, despite the fact that Brca1-⌬11 lacks previously defined nuclear localization signals. However, we further show that DNA damage-induced phosphorylation of Brca1-⌬11 is significantly reduced compared to full-length Brca1, and that gamma irradiation-induced Rad51 focus formation is impaired in cells in which only Brca1-⌬11 is expressed. Our results suggest that the increased viability of embryos bearing homozygous deletions of exon 11 may be due to expression of Brca1-⌬11 and suggest an explanation for the genomic instability that accompanies the loss of full-length Brca1.Germ line mutations in BRCA1 predispose women to earlyonset breast and ovarian cancers (18,38). The BRCA1 gene is composed of 23 exons that encode a 1,863-amino-acid fulllength protein, over half of which is encoded by an unusually large exon, exon 11, which is 3.4 kb in length. In addition to the full-length BRCA1 protein, p220 BRCA1 , human cells contain alternatively spliced variants referred to as BRCA1-⌬11 (referred to here as p97 BRCA1 ) and BRCA1-⌬11b (referred to here as p110 BRCA1 ), which lack all and most of exon 11, respectively (54, 58). These isoforms arise from in-frame splicing events and retain the highly conserved amino-terminal RING finger and carboxyl-terminal BRCT domains found in fulllength BRCA1 but lack the nuclear localization signals previously identified in exon 11 (11,54,58). The abundant expression of p97 BRCA1 and p110 BRCA1 has been demonstrated in a variety of adult tissues, including the human mammary gland, in which transcripts encoding p110 BRCA1 are expressed at levels comparable to those encoding p220 BRCA1 (33,54,58). The observation that human BRCA1 is phosphorylated in response to UV light, ionizing radiation, and other agents that damage DNA, and the identification of BRCA1-interacting proteins such as RAD51 and RAD50-Mre11-p95 complexes that colocalize with BRCA1 following DNA damage have suggested a role for BRCA1 in DNA r...