Germ-line mutations in breast cancer susceptibility gene, BRCA1, result in 
familial predisposition to breast and ovarian cancers. The BRCA1 protein has 
multiple functional domains that interact with a variety of proteins in multiple 
cellular processes. Understanding the biological consequences of BRCA1 
interactions with its binding partners is important for elucidating its 
tissue-specific tumor suppression function. The Cofactor of BRCA1 (COBRA1) is a 
BRCA1-binding protein that, as a component of negative elongation factor (NELF), 
regulates RNA polymerase II pausing during transcription elongation. We recently 
identified a genetic interaction between mouse Brca1 and Cobra1 that 
antagonistically regulates mammary gland development. However, it remains 
unclear which of the myriad functions of Brca1 are required for its genetic 
interaction with Cobra1. Here, we show that, unlike deletion of Brca1 exon 11, 
separation-of-function mutations that abrogate either the E3 ligase activity of 
its RING domain or the phospho-recognition property of its BRCT domain are not 
sufficient to rescue the mammary developmental defects in Cobra1 knockout mice. 
Furthermore, deletion of mouse Palb2, another breast cancer susceptibility gene 
with functional similarities to BRCA1, does not rescue Cobra1 
knockout-associated mammary defects. Thus, the Brca1/Cobra1 genetic interaction 
is both domain- and gene-specific in the context of mammary gland development.