Abstract
The breast cancer susceptibility gene BRCA1 is well known for its function in double-strand break (DSB) DNA repair. While BRCA1 is also implicated in transcriptional regulation, the physiological significance remains unclear. COBRA1 (also known as NELF-B) is a BRCA1-binding protein that regulates RNA polymerase II (RNAPII) pausing and transcription elongation. Here we interrogate functional interaction between BRCA1 and COBRA1 during mouse mammary gland development. Tissue-specific deletion of Cobra1 reduces mammary epithelial compartments and blocks ductal morphogenesis, alveologenesis and lactogenesis, demonstrating a pivotal role of COBRA1 in adult tissue development. Remarkably, these developmental deficiencies due to Cobra1 knockout are largely rescued by additional loss of full-length Brca1. Furthermore, Brca1/Cobra1 double knockout restores developmental transcription at puberty, alters luminal epithelial homoeostasis, yet remains deficient in homologous recombination-based DSB repair. Thus our genetic suppression analysis uncovers a previously unappreciated, DNA repair-independent function of BRCA1 in antagonizing COBRA1-dependent transcription programme during mammary gland development.
Highlights
The breast cancer susceptibility gene BRCA1 is well known for its function in double-strand break (DSB) DNA repair
To investigate the role of COBRA1 in mammary gland development, we generated mammary epithelium-specific KO mice by breeding the MMTV-Cre strain[29] with Cobra1f/f animals[26], which resulted in deletion of the first four Cobra[1] exons
Our mouse genetic study unequivocally demonstrates an important role of the COBRA1 in mammary gland development
Summary
The breast cancer susceptibility gene BRCA1 is well known for its function in double-strand break (DSB) DNA repair. COBRA1 ( known as NELF-B) is a BRCA1-binding protein that regulates RNA polymerase II (RNAPII) pausing and transcription elongation. BRCA1 binds to RNA polymerase II (RNAPII)[5] and various site-specific transcription factors, including oestrogen receptor a (ERa) and GATA3 (refs 6,7), which are involved in mammary gland development and breast cancer. Consistent with a role for BRCA1 in transcriptional regulation, genome-wide analysis indicates that chromatin binding of BRCA1 is enriched at transcription start sites (TSS) across the human genome[13,14,15] Notwithstanding these in vitro findings, there is a gap of knowledge concerning the physiological relevance of these transcription-related activities of BRCA1 in vivo. Using mammary epithelium-specific knockout (KO) mouse models for Brca[1] and Cobra[1], we provide compelling genetic evidence for a previously unrecognized functional link between BRCA1 and a transcription elongation factor in dictating the developmental outcome in mammary epithelium
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