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Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11467-72. doi: 10.1073/pnas.1317751111. Epub 2014 Jul 21.

PAPD5-mediated 3' adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease.

Author information

1
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;
2
Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 Huddinge, Sweden;
3
RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045, Japan;
4
Division of Oncology, Department of Clinical Sciences, Lund University Cancer Center/Medicon Village, SE-223 81 Lund, Sweden;
5
Department of Obstetrics and Gynecology and Center for Reproductive Medicine.
6
Department of Molecular and Cellular Biology, and.
7
Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan;
8
Departments of Anti-Aging Medicine andGeriatric Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan;
9
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;
10
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;
11
RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;
12
Department of Systems Bioinformatics, Amsterdam Institute for Molecules, Medicines and Systems, VU University Amsterdam, 1081 HV, Amsterdam, The Netherlands;
13
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;
14
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030;Department of Biology and Biochemistry, University of Houston, Houston, TX 77204; and.
15
RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan;RIKEN Preventive Medicine and Diagnosis Innovation Program, Wako, Saitama 351-0198, Japan.
16
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.

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.

KEYWORDS:

microRNA processing; nucleotidyl transferase

PMID:
25049417
PMCID:
PMC4128123
DOI:
10.1073/pnas.1317751111
[Indexed for MEDLINE]
Free PMC Article

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