title: PARN deadenylase is involved in miRNA-dependent degradation of TP53 mRNA in mammalian cells.
abstract: mRNA deadenylation is under the control of cis-acting regulatory elements, which include AU-rich elements (AREs) and microRNA (miRNA) targeting sites, within the 3' untranslated region (3' UTRs) of eukaryotic mRNAs. Deadenylases promote miRNA-induced mRNA decay through their interaction with miRNA-induced silencing complex (miRISC). However, the role of poly(A) specific ribonuclease (PARN) deadenylase in miRNA-dependent mRNA degradation has not been elucidated. Here, we present evidence that not only ARE- but also miRNA-mediated pathways are involved in PARN-mediated regulation of the steady state levels of TP53 mRNA, which encodes the tumor suppressor p53. Supporting this, Argonaute-2 (Ago-2), the core component of miRISC, can coexist in complexes with PARN resulting in the activation of its deadenylase activity. PARN regulates TP53 mRNA stability through not only an ARE but also an adjacent miR-504/miR-125b-targeting site in the 3' UTR. More importantly, we found that miR-125b-loaded miRISC contributes to the specific recruitment of PARN to TP53 mRNA, and that can be reverted by the ARE-binding protein HuR. Together, our studies provide new insights into the role of PARN in miRNA-dependent control of mRNA decay and into the mechanisms behind the regulation of p53 expression.
authors.affiliation: Chemistry Department, Belfer Research Building, Hunter College and Graduate Center, City University of New York, New York, NY 10021, USA.
authors.forename: Xiaokan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Chemistry Department, Belfer Research Building, Hunter College and Graduate Center, City University of New York, New York, NY 10021, USA Department of Biological Sciences, Kingsborough Community College, City University of New York, 2001 Oriental Boulevard, Brooklyn, NY 11235, USA.
authors.forename: Emral
authors.initials: E
authors.lastname: Devany
authors.affiliation: Chemistry Department, Belfer Research Building, Hunter College and Graduate Center, City University of New York, New York, NY 10021, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Murphy
authors.affiliation: Chemistry Department, Belfer Research Building, Hunter College and Graduate Center, City University of New York, New York, NY 10021, USA.
authors.forename: Galina
authors.initials: G
authors.lastname: Glazman
authors.affiliation: Chemistry Department, Belfer Research Building, Hunter College and Graduate Center, City University of New York, New York, NY 10021, USA.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Persaud
authors.affiliation: Chemistry Department, Belfer Research Building, Hunter College and Graduate Center, City University of New York, New York, NY 10021, USA fkleiman@hunter.cuny.edu.
authors.forename: Frida E
authors.initials: FE
authors.lastname: Kleiman
mesh_terms: D020413:3' Untranslated Regions; D060565:Argonaute Proteins / Q000378:metabolism; D002460:Cell Line; D000067780:ELAV-Like Protein 1 / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C466422:AGO2 protein, human; D060565:Argonaute Proteins; D000067780:ELAV-Like Protein 1; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D012260:Ribonucleases; C445084:mRNA deadenylase