title: PAPD5-mediated 3' adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease.
abstract: Next-generation sequencing experiments have shown that microRNAs (miRNAs) are expressed in many different isoforms (isomiRs), whose biological relevance is often unclear. We found that mature miR-21, the most widely researched miRNA because of its importance in human disease, is produced in two prevalent isomiR forms that differ by 1 nt at their 3' end, and moreover that the 3' end of miR-21 is posttranscriptionally adenylated by the noncanonical poly(A) polymerase PAPD5. PAPD5 knockdown caused an increase in the miR-21 expression level, suggesting that PAPD5-mediated adenylation of miR-21 leads to its degradation. Exoribonuclease knockdown experiments followed by small-RNA sequencing suggested that PARN degrades miR-21 in the 3'-to-5' direction. In accordance with this model, microarray expression profiling demonstrated that PAPD5 knockdown results in a down-regulation of miR-21 target mRNAs. We found that disruption of the miR-21 adenylation and degradation pathway is a general feature in tumors across a wide range of tissues, as evidenced by data from The Cancer Genome Atlas, as well as in the noncancerous proliferative disease psoriasis. We conclude that PAPD5 and PARN mediate degradation of oncogenic miRNA miR-21 through a tailing and trimming process, and that this pathway is disrupted in cancer and other proliferative diseases.
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;Department of Systems Bioinformatics, Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam, 1081 HV, Amsterdam, The Netherlands;
authors: Joost
authors: http://orcid.org/0000-0002-7183-9650
authors: J
authors: Boele
authors: Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 Huddinge, Sweden;
authors: Helena
authors: H
authors: Persson
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan;
authors: Jay W
authors: JW
authors: Shin
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan;
authors: Yuri
authors: Y
authors: Ishizu
authors: Division of Oncology, Department of Clinical Sciences, Lund University Cancer Center/Medicon Village, SE-223 81 Lund, Sweden;
authors: Inga S
authors: IS
authors: Newie
authors: Division of Oncology, Department of Clinical Sciences, Lund University Cancer Center/Medicon Village, SE-223 81 Lund, Sweden;
authors: Rolf
authors: R
authors: Søkilde
authors: Department of Obstetrics and Gynecology and Center for Reproductive Medicine.
authors: Shannon M
authors: SM
authors: Hawkins
authors: Department of Molecular and Cellular Biology, and.
authors: Cristian
authors: C
authors: Coarfa
authors: Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan;
authors: Kazuhiro
authors: K
authors: Ikeda
authors: Departments of Anti-Aging Medicine andGeriatric Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan;
authors: Ken-ichi
authors: K
authors: Takayama
authors: Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan;
authors: Kuniko
authors: K
authors: Horie-Inoue
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205;
authors: Yoshinari
authors: Y
authors: Ando
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894;
authors: A Maxwell
authors: AM
authors: Burroughs
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;
authors: Chihiro
authors: C
authors: Sasaki
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;
authors: Chizuru
authors: C
authors: Suzuki
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan;
authors: Mizuho
authors: M
authors: Sakai
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan;
authors: Shintaro
authors: S
authors: Aoki
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;
authors: Ayumi
authors: A
authors: Ogawa
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan;
authors: Akira
authors: A
authors: Hasegawa
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan;
authors: Marina
authors: M
authors: Lizio
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan;
authors: Kaoru
authors: K
authors: Kaida
authors: Department of Systems Bioinformatics, Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam, 1081 HV, Amsterdam, The Netherlands;
authors: Bas
authors: B
authors: Teusink
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan;
authors: Piero
authors: P
authors: Carninci
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan;
authors: Harukazu
authors: H
authors: Suzuki
authors: Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan;Departments of Anti-Aging Medicine andGeriatric Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan;
authors: Satoshi
authors: S
authors: Inoue
authors: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030;Department of Biology and Biochemistry, University of Houston, Houston, TX 77204; and.
authors: Preethi H
authors: PH
authors: Gunaratne
authors: Division of Oncology, Department of Clinical Sciences, Lund University Cancer Center/Medicon Village, SE-223 81 Lund, Sweden;
authors: Carlos
authors: C
authors: Rovira
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama 351-0198, Japan.
authors: Yoshihide
authors: Y
authors: Hayashizaki
authors: RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan; mdehoon@gsc.riken.jp.
authors: Michiel J L
authors: MJ
authors: de Hoon
mesh_terms: D000225:Adenine / Q000378:metabolism*; D001483:Base Sequence; D003596:Cytosine / Q000378:metabolism; D005095:Exoribonucleases / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009690:Nucleic Acid Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012316:RNA Nucleotidyltransferases / Q000378:metabolism*; D020871:RNA Stability; D043244:Ribonuclease III / Q000378:metabolism
chemical_list: D000225:Adenine; D003596:Cytosine; D005095:Exoribonucleases; D035683:MicroRNAs; D020033:Protein Isoforms; D012316:RNA Nucleotidyltransferases; D043244:Ribonuclease III; C524940:MIRN21 microRNA, human; C567954:TENT4B protein, human
keywords: microRNA processing; nucleotidyl transferase