title: The F-box protein FBXO44 mediates BRCA1 ubiquitination and degradation.
abstract: BRCA1 mutations account for a significant proportion of familial breast and ovarian cancers. In addition, reduced BRCA1 protein is associated with sporadic cancer cases in these tissues. At the cellular level, BRCA1 plays a critical role in multiple cellular functions such as DNA repair and cell cycle checkpoint control. Its protein level is regulated in a cell cycle-dependent manner. However, regulation of BRCA1 protein stability is not fully understood. Our earlier study showed that the amino terminus of BRCA1 harbors a degron sequence that is sufficient and necessary for conferring BRCA1 degradation. In the current study, we used mass spectrometry to identify Skp1 that regulates BRCA1 protein stability. Small interfering RNA screening that targets all human F-box proteins uncovered FBXO44 as an important protein that influences BRCA1 protein level. The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro. Furthermore, the N terminus of BRCA1 mediates the interaction between BRCA1 and FBXO44. Overexpression of SCF(FBXO44) reduces BRCA1 protein level. Taken together, our work strongly suggests that SCF(FBXO44) is an E3 ubiquitin ligase responsible for BRCA1 degradation. In addition, FBXO44 expression pattern in breast carcinomas suggests that SCF(FBXO44)-mediated BRCA1 degradation might contribute to sporadic breast tumor development.
authors.affiliation: Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Yunzhe
authors.initials: Y
authors.lastname: Lu
authors.forename: Jiezhi
authors.initials: J
authors.lastname: Li
authors.forename: Dongmei
authors.initials: D
authors.lastname: Cheng
authors.forename: Balaji
authors.initials: B
authors.lastname: Parameswaran
authors.forename: Shaohua
authors.initials: S
authors.lastname: Zhang
authors.forename: Zefei
authors.initials: Z
authors.lastname: Jiang
authors.forename: P Renee
authors.initials: PR
authors.lastname: Yew
authors.forename: Junmin
authors.initials: J
authors.lastname: Peng
authors.forename: Qinong
authors.initials: Q
authors.lastname: Ye
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Hu
mesh_terms: D019313:BRCA1 Protein / Q000737:chemistry*; D001943:Breast Neoplasms / Q000378:metabolism*; D002453:Cell Cycle; D004260:DNA Repair; D044783:F-Box Proteins / Q000737:chemistry* / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D044783:F-Box Proteins; C578089:FBXO44 protein, human; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; C097351:SKP1 protein, human; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases