title: DGCR8-mediated disruption of miRNA biogenesis induces cellular senescence in primary fibroblasts.
abstract: The regulation of gene expression by microRNAs (miRNAs) is critical for normal development and physiology. Conversely, miRNA function is frequently impaired in cancer, and other pathologies, either by aberrant expression of individual miRNAs or dysregulation of miRNA synthesis. Here, we have investigated the impact of global disruption of miRNA biogenesis in primary fibroblasts of human or murine origin, through the knockdown of DGCR8, an essential mediator of the synthesis of canonical miRNAs. We find that the inactivation of DGCR8 in these cells results in a dramatic antiproliferative response, with the acquisition of a senescent phenotype. Senescence triggered by DGCR8 loss is accompanied by the upregulation of the cell-cycle inhibitor p21CIP1. We further show that a subset of senescence-associated miRNAs with the potential to target p21CIP1 is downregulated during DGCR8-mediated senescence. Interestingly, the antiproliferative response to miRNA biogenesis disruption is retained in human tumor cells, irrespective of p53 status. In summary, our results show that defective synthesis of canonical microRNAs results in cell-cycle arrest and cellular senescence in primary fibroblasts mediated by specific miRNAs, and thus identify global miRNA disruption as a novel senescence trigger.
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols' CSIC-UAM, Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gómez-Cabello
authors.forename: Isabel
authors.initials: I
authors.lastname: Adrados
authors.forename: David
authors.initials: D
authors.lastname: Gamarra
authors.forename: Hikaru
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takatsu
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takatsu
authors.forename: Jesús
authors.initials: J
authors.lastname: Gil
authors.forename: Ignacio
authors.initials: I
authors.lastname: Palmero
mesh_terms: D048708:Cell Growth Processes / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics*; D011506:Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D015854:Up-Regulation
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C474043:DGCR8 protein, human; D035683:MicroRNAs; D011506:Proteins; D016601:RNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: DGCR8; fibroblasts; microRNA; p21CIP1; p53; senescence