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

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 prev...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 31; pp. 11467 - 11472
Main Authors:	Boele, Joost, Persson, Helena, Shin, Jay W., Ishizu, Yuri, Newie, Inga S., Søkilde, Rolf, Hawkins, Shannon M., Coarfa, Cristian, Ikeda, Kazuhiro, Takayama, Ken-ichi, Horie-Inoue, Kuniko, Ando, Yoshinari, Burroughs, A. Maxwell, Sasaki, Chihiro, Suzuki, Chizuru, Sakai, Mizuho, Aoki, Shintaro, Ogawa, Ayumi, Hasegawa, Akira, Lizio, Marina, Kaida, Kaoru, Teusink, Bas, Carninci, Piero, Suzuki, Harukazu, Inoue, Satoshi, Gunaratne, Preethi H., Rovira, Carlos, Hayashizaki, Yoshihide, de Hoon, Michiel J. L.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 05-08-2014 National Acad Sciences
Subjects:	Adenine - metabolism Base Sequence Biological Sciences Cancer Cancer and Oncology Cancer och onkologi Cell lines Clinical Medicine Cytosine - metabolism Exoribonucleases - metabolism Experiments Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Genomes Genomics High-Throughput Nucleotide Sequencing Humans Klinisk medicin MCF-7 Cells Medical and Health Sciences Medicin och hälsovetenskap Messenger RNA MicroRNA MicroRNAs - chemistry MicroRNAs - genetics MicroRNAs - metabolism Models, Biological Molecular biology Molecular Sequence Data Neoplasms - genetics Neoplasms - pathology Nucleic Acid Conformation Nucleotides Protein Isoforms - chemistry Protein Isoforms - genetics Protein Isoforms - metabolism Psoriasis Ribonuclease III - metabolism Ribonucleic acid RNA RNA Nucleotidyltransferases - metabolism RNA Stability Sequencing Tumors microRNA processing nucleotidyl transferase
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Summary:	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.
Bibliography:	http://dx.doi.org/10.1073/pnas.1317751111 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 1Present address: Division of Oncology, Department of Clinical Sciences, Lund University Cancer Center/Medicon Village, SE-223 81 Lund, Sweden. Edited by David P. Bartel, Massachusetts Institute of Technology, Cambridge, MA, and approved June 23, 2014 (received for review September 21, 2013) Author contributions: S.I., Y.H., and M.J.L.d.H. designed research; H.P., J.W.S., Y.I., I.S.N., R.S., K.I., K.-i.T., K.H.-I., Y.A., C. Sasaki, C. Suzuki, M.S., S.A., A.O., A.H., M.L., K.K., and C.R. performed research; J.B., C.C., and M.J.L.d.H. analyzed data; and J.B., H.P., S.M.H., A.M.B., B.T., P.C., H.S., P.H.G., C.R., and M.J.L.d.H. wrote the paper.
ISSN:	0027-8424 1091-6490 1091-6490
DOI:	10.1073/pnas.1317751111