title: Mutant p53 inhibits miRNA biogenesis by interfering with the microprocessor complex.
abstract: Downregulation of microRNAs (miRNAs) is commonly observed in cancers and promotes tumorigenesis suggesting that miRNAs may function as tumor suppressors. However, the mechanism through which miRNAs are regulated in cancer, and the connection between oncogenes and miRNA biogenesis remain poorly understood. The TP53 tumor-suppressor gene is mutated in half of human cancers resulting in an oncogene with gain-of-function activities. Here we demonstrate that mutant p53 (mutp53) oncoproteins modulate the biogenesis of a subset of miRNAs in cancer cells inhibiting their post-transcriptional maturation. Interestingly, among these miRNAs several are also downregulated in human tumors. By confocal, co-immunoprecipitation and RNA-chromatin immunoprecipitation experiments, we show that endogenous mutp53 binds and sequesters RNA helicases p72/82 from the microprocessor complex, interfering with Drosha-pri-miRNAs association. In agreement with this, the overexpression of p72 leads to an increase of mature miRNAs levels. Moreover, functional experiments demonstrate the oncosuppressive role of mutp53-dependent miRNAs (miR-517a, -519a, -218, -105). Our study highlights a previously undescribed mechanism by which mutp53 interferes with Drosha-p72/82 association leading, at least in part, to miRNA deregulation observed in cancer.
authors.affiliation: Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Garibaldi
authors.affiliation: Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Falcone
authors.affiliation: Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Trisciuoglio
authors.affiliation: Institute for System Analysis and Computer Science "Antonio Ruberti", National Research Council, Rome, Italy.|SysBio Centre for Systems Biology, Rome, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Colombo
authors.affiliation: Laboratorio Nazionale CIB, Area Science Park Padriciano, Trieste, Italy.|Dipartimento di Scienze della Vita-Università degli Studi di Trieste, Trieste, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Lisek
authors.affiliation: Laboratorio Nazionale CIB, Area Science Park Padriciano, Trieste, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Walerych
authors.affiliation: Laboratorio Nazionale CIB, Area Science Park Padriciano, Trieste, Italy.|Dipartimento di Scienze della Vita-Università degli Studi di Trieste, Trieste, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Del Sal
authors.affiliation: Institute for System Analysis and Computer Science "Antonio Ruberti", National Research Council, Rome, Italy.|SysBio Centre for Systems Biology, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Paci
authors.affiliation: Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy.|Department of Research, Advanced Diagnostics, and Technological Innovation, Laboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Bossi
authors.affiliation: Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Piaggio
authors.affiliation: Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gurtner
mesh_terms: D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; C102004:DDX17 protein, human; D053487:DEAD-box RNA Helicases