title: Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development.
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.
authors.affiliation: Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Sreejith J
authors.initials: SJ
authors.lastname: Nair
authors.affiliation: Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Huai-Chin
authors.initials: HC
authors.lastname: Chiang
authors.affiliation: Department of Computer Science, The University of Texas at San Antonio, San Antonio, Texas 78249, USA.
authors.forename: Md Jamiul
authors.initials: MJ
authors.lastname: Jahid
authors.affiliation: Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Garza
authors.affiliation: Research and Development, Illumina, Inc., San Diego, California 92122, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: April
authors.affiliation: Research and Development, Illumina, Inc., San Diego, California 92122, USA.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Salathia
authors.affiliation: Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Tapahsama
authors.initials: T
authors.lastname: Banerjee
authors.affiliation: Department of Computer Science, The University of Texas at San Antonio, San Antonio, Texas 78249, USA.
authors.forename: Fahad S
authors.initials: FS
authors.lastname: Alenazi
authors.affiliation: Department of Computer Science, The University of Texas at San Antonio, San Antonio, Texas 78249, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Ruan
authors.affiliation: Research and Development, Illumina, Inc., San Diego, California 92122, USA.
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.affiliation: Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Parvin
authors.affiliation: Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Victor X
authors.initials: VX
authors.lastname: Jin
authors.affiliation: Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
mesh_terms: D000375:Aging; D000818:Animals; D019313:BRCA1 Protein; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology*; D004847:Epithelial Cells; D004967:Estrogens / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006706:Homeostasis; D008321:Mammary Glands, Animal / Q000254:growth & development*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011372:Progestins / Q000378:metabolism; D016601:RNA-Binding Proteins; D012741:Sexual Maturation; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C000605931:Brca1 protein, mouse; C541978:Cobra1 protein, mouse; D004967:Estrogens; D009687:Nuclear Proteins; D011372:Progestins; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins