Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development

Nat Commun. 2016 Mar 4:7:10913. doi: 10.1038/ncomms10913.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging
  • Animals
  • BRCA1 Protein
  • DNA Breaks, Double-Stranded
  • DNA Repair / physiology*
  • Epithelial Cells
  • Estrogens / metabolism
  • Female
  • Gene Expression Regulation, Developmental / physiology
  • Homeostasis
  • Mammary Glands, Animal / growth & development*
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Progestins / metabolism
  • RNA-Binding Proteins
  • Sexual Maturation
  • Transcriptome
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • BRCA1 Protein
  • Brca1 protein, mouse
  • Cobra1 protein, mouse
  • Estrogens
  • Nuclear Proteins
  • Progestins
  • RNA-Binding Proteins
  • Tumor Suppressor Proteins