53 BP 1 ablation rescues genomic instability in mice expressing ‘ RING ‐less’ BRCA 1

BRCA 1 mutations strongly predispose affected individuals to breast and ovarian cancer, but the mechanism by which BRCA 1 acts as a tumor suppressor is not fully understood. Homozygous deletion of exon 2 of the mouse Brca1 gene normally causes embryonic lethality, but we show that exon 2‐deleted alleles of Brca1 are expressed as a mutant isoform that lacks the N‐terminal RING domain. This “ RING ‐less” BRCA 1 protein is stable and efficiently recruited to the sites of DNA damage. Surprisingly, robust RAD 51 foci form in cells expressing RING ‐less BRCA 1 in response to DNA damage, but the cells nonetheless display the substantial genomic instability. Genomic instability can be rescued by the deletion of Trp53bp1 , which encodes the DNA damage response factor 53 BP 1, and mice expressing RING ‐less BRCA 1 do not show an increased susceptibility to tumors in the absence of 53 BP 1. Genomic instability in cells expressing RING ‐less BRCA 1 correlates with the loss of BARD 1 and a defect in restart of replication forks after hydroxyurea treatment, suggesting a role of BRCA 1– BARD 1 in genomic integrity that is independent of RAD 51 loading.