title: Rb-associated protein 46 (RbAp46) inhibits transcriptional transactivation mediated by BRCA1.
abstract: The retinoblastoma suppressor (Rb)-associated protein 46 (RbAp46) is a member of the WD-repeat protein family and a component of the histone modifying and remodeling complexes. Previously, we demonstrated that RbAp46 is a potent growth inhibitor that can suppress the transformed phenotype of tumor cells. To explore the molecular mechanisms of RbAp46 function, we used RbAp46 as a bait in a yeast two-hybrid screening and found that RbAp46 interacts specifically with the C-terminal region of BRCA1 (the BRCT domain), a domain involved in the t transactivation activity of BRCA1. Coimmunoprecipitation assays demonstrated that the interaction of RbAp46 with BRCA1 requires the first two of the four Trp-Asp (WD)-repeats of RbAp46. We also showed that expression of RbAp46 represses the transactivation activity mediated by the BRCT/Gal4 fusion protein and inhibits the transactivation of the p21 promoter mediated by the full-length BRCA1. Interestingly, the association of BRCA1 and RbAp46 is disrupted in cells treated with DNA-damaging agents. These results suggest that RbAp46 may specifically interact with BRCA1 and modulate its transactivation activity in response to DNA damage.
authors.affiliation: Division of Growth Regulation, Department of Medicine, Beth Israel-Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: G C
authors.initials: GC
authors.lastname: Chen
authors.forename: L S
authors.initials: LS
authors.lastname: Guan
authors.forename: J H
authors.initials: JH
authors.lastname: Yu
authors.forename: G C
authors.initials: GC
authors.lastname: Li
authors.forename: H R
authors.initials: HR
authors.lastname: Choi Kim
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Wang
mesh_terms: D019313:BRCA1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005720:Gamma Rays; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D056524:Retinoblastoma-Binding Protein 7; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D020798:Two-Hybrid System Techniques
chemical_list: D019313:BRCA1 Protein; D002352:Carrier Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; C490746:RBBP7 protein, human; D011993:Recombinant Fusion Proteins; D056524:Retinoblastoma-Binding Protein 7; D014157:Transcription Factors; D004317:Doxorubicin