Gene-Specific Genetic Complementation between Brca1 and Cobra1 During Mouse Mammary Gland Development

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.