title: miR-19, a component of the oncogenic miR-17∼92 cluster, targets the DNA-end resection factor CtIP.
abstract: MicroRNA-19 (miR-19) was recently identified as the key oncogenic component of the polycistronic miR-17∼92 cluster, also known as oncomiR-1, which is frequently upregulated or amplified in multiple tumor types. However, the gene targets and the pathways underlying the tumor-promoting activity of miR-19 still remain largely elusive. CtIP/RBBP8 promotes DNA-end resection, a critical step in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR), and is considered to function as a tumor suppressor. In this study, we show that miR-19 downregulates CtIP expression by binding to two highly conserved sequences located in the 3'-untranslated region of CtIP mRNA. We further demonstrate that CtIP expression is repressed by miR-19 during continuous genotoxic stress in a p53-dependent manner. Finally, we report that miR-19 impairs CtIP-mediated DNA-end resection, which results in reduced HR levels and DNA damage hypersensitivity. By downregulating CtIP, miR-19 overexpression suppresses the faithful repair of DSBs that is crucial for genome maintenance. Our findings thus provide new mechanistic insight into the oncogenic role of the miR-17∼92 cluster.
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Hühn
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen N, Denmark.
authors.forename: A N
authors.initials: AN
authors.lastname: Kousholt
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen N, Denmark.
authors.forename: C S
authors.initials: CS
authors.lastname: Sørensen
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
authors.forename: A A
authors.initials: AA
authors.lastname: Sartori
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D015536:Down-Regulation; D004706:Endodeoxyribonucleases; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D008969:Molecular Sequence Data; D005810:Multigene Family; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference
chemical_list: D020413:3' Untranslated Regions; D002352:Carrier Proteins; C549214:MIRN19A microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human