title: Translational control of TOP2A influences doxorubicin efficacy.
abstract: The cellular abundance of topoisomerase IIα (TOP2A) critically maintains DNA topology after replication and determines the efficacy of TOP2 inhibitors in chemotherapy. Here, we report that the RNA-binding protein HuR, commonly overexpressed in cancers, binds to the TOP2A 3'-untranslated region (3'UTR) and increases TOP2A translation. Reducing HuR levels triggered the recruitment of TOP2A transcripts to RNA-induced silencing complex (RISC) components and to cytoplasmic processing bodies. Using a novel MS2-tagged RNA precipitation method, we identified microRNA miR-548c-3p as a mediator of these effects and further uncovered that the interaction of miR-548c-3p with the TOP2A 3'UTR repressed TOP2A translation by antagonizing the action of HuR. Lowering TOP2A by silencing HuR or by overexpressing miR-548c-3p selectively decreased DNA damage after treatment with the chemotherapeutic agent doxorubicin. In sum, HuR enhances TOP2A translation by competing with miR-548c-3p; their combined actions control TOP2A expression levels and determine the effectiveness of doxorubicin.
authors.affiliation: Laboratory of Molecular Biology and Immunology, NIA-IRP, NIH, Baltimore, Maryland 21224, USA.
authors.forename: Subramanya
authors.initials: S
authors.lastname: Srikantan
authors.forename: Kotb
authors.initials: K
authors.lastname: Abdelmohsen
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Lee
authors.forename: Kumiko
authors.initials: K
authors.lastname: Tominaga
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Subaran
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kuwano
authors.forename: Ritu
authors.initials: R
authors.lastname: Kulshrestha
authors.forename: Rohit
authors.initials: R
authors.lastname: Panchakshari
authors.forename: Hyeon Ho
authors.initials: HH
authors.lastname: Kim
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Yang
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Martindale
authors.forename: Bernard S
authors.initials: BS
authors.lastname: Marasa
authors.forename: Mihee M
authors.initials: MM
authors.lastname: Kim
authors.forename: Robert P
authors.initials: RP
authors.lastname: Wersto
authors.forename: Fred E
authors.initials: FE
authors.lastname: Indig
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chowdhury
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
mesh_terms: D020413:3' Untranslated Regions; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics*; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology*; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D014176:Protein Biosynthesis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034743:RNA-Induced Silencing Complex / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D004268:DNA-Binding Proteins; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C561887:MIRN548 microRNA, human; D035683:MicroRNAs; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D034743:RNA-Induced Silencing Complex; D004317:Doxorubicin; D004247:DNA; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human