title: BRCA1 regulates microRNA biogenesis via the DROSHA microprocessor complex.
abstract: MicroRNAs (miRNAs) are noncoding RNAs that function as key posttranscriptional regulators of gene expression. miRNA maturation is controlled by the DROSHA microprocessor complex. However, the detailed mechanism of miRNA biogenesis remains unclear. We show that the tumor suppressor breast cancer 1 (BRCA1) accelerates the processing of miRNA primary transcripts. BRCA1 increased the expressions of both precursor and mature forms of let-7a-1, miR-16-1, miR-145, and miR-34a. In addition, this tumor suppressor was shown to be directly associated with DROSHA and DDX5 of the DROSHA microprocessor complex, and it interacted with Smad3, p53, and DHX9 RNA helicase. We also found that BRCA1 recognizes the RNA secondary structure and directly binds with primary transcripts of miRNAs via a DNA-binding domain. Together, these results suggest that BRCA1 regulates miRNA biogenesis via the DROSHA microprocessor complex and Smad3/p53/DHX9. Our findings also indicate novel functions of BRCA1 in miRNA biogenesis, which may be linked to its tumor suppressor mechanism and maintenance of genomic stability.
authors.affiliation: Department of Oral Frontier Biology, Center for Frontier Oral Science, Osaka University Graduate School of Dentistry, Osaka 565-0871, Japan. skawai@dent.osaka-u.ac.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Kawai
authors.forename: Atsuo
authors.initials: A
authors.lastname: Amano
mesh_terms: D019313:BRCA1 Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D043244:Ribonuclease III / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004268:DNA-Binding Proteins; C541010:MIRN145 microRNA, human; C505362:MIRN16 microRNA, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016159:Tumor Suppressor Protein p53; C487931:mirnlet7 microRNA, human; C517918:DROSHA protein, human; D043244:Ribonuclease III; C098487:DHX9 protein, human; C506749:Ddx5 protein, human; D053487:DEAD-box RNA Helicases