Brca1 Conditional Knockout mouse models

Brca1, mouse ortholog of human BRCA1, encodes a RING domain E3 ubiquitin ligase that heterodimerizes obligately with BARD1 and uses tandem BRCT repeats to read phosphopeptides on ABRAXAS, BACH1 and CTIP, assembling distinct complexes that antagonize 53BP1 and shieldin at break ends, license end resection, and promote RAD51 loading for homologous recombination. Loss produces the BRCAness state of HR deficiency, replication fork instability and PARP inhibitor sensitivity, with tumor spectra concentrated in mammary and ovarian epithelium. Homozygous null mice die during early embryogenesis, rescued partially by Trp53 loss, so conditional exon 11 or full null floxed alleles combined with mammary Cre drivers and a p53 allele constitute the canonical model. Separation-of-function knockins, notably RING-deficient and BRCT phospho-binding mutants, distinguish ligase activity from scaffolding and explain PARP inhibitor resistance through 53BP1 loss. Choose conditional nulls for tumorigenesis and drug response, and precise variant knockins for clinical variant reclassification, always pairing with a validated epithelial Cre.

Tissue restricted knockout of Brca1 keeps wild type function everywhere else. Breeding is often more robust, and the setup mirrors patient biology where mutations arise in a subset of cells.