Dataset Information

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.

SUBMITTER: Boele J

PROVIDER: S-EPMC4128123 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Boele Joost J Persson Helena H Shin Jay W JW Ishizu Yuri Y Newie Inga S IS Søkilde Rolf R Hawkins Shannon M SM Coarfa Cristian C Ikeda Kazuhiro K Takayama Ken-ichi K Horie-Inoue Kuniko K Ando Yoshinari Y Ando Yoshinari Y Burroughs A Maxwell AM Sasaki Chihiro C Suzuki Chizuru C Sakai Mizuho M Aoki Shintaro S Ogawa Ayumi A Hasegawa Akira A Lizio Marina M Kaida Kaoru K Teusink Bas B Carninci Piero P Suzuki Harukazu H Inoue Satoshi S Gunaratne Preethi H PH Rovira Carlos C Hayashizaki Yoshihide Y de Hoon Michiel J L MJ

Proceedings of the National Academy of Sciences of the United States of America 20140721 31

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 ...[more]

PMID: 25049417

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Project description:BACKGROUND:Due to the lack of research on the pathological mechanism of temporomandibular joint osteoarthritis (TMJOA), there are few effective treatment measures in the clinic. In recent years, microRNAs (miRs) have been demonstrated to play an important role in the pathogenesis of osteoarthritis (OA) by regulating a variety of target genes, and the latest evidence shows that miR-21-5p is specifically overexpressed in OA. The purpose of this project was to clarify whether miR-21-5p can regulate the TMJOA process by targeting Spry1. METHODS:TMJOA was induced by a unilateral anterior crossbite (UAC) model, and the effect of miR-21-5p knockout on TMJOA was evaluated by toluidine blue (TB), immunohistochemical (IHC) staining, Western blotting (WB) and RT-qPCR. Primary mouse condylar chondrocytes (MCCs) were isolated, cultured and transfected with a series of mimics, inhibitors, siRNA-Spry1 or cDNA Spry1. WB, RT-qPCR, IHC and TB were used to detect the effect of miR-21-5p and its target gene Spry1 on the expression of MMP-13, VEGF and p-ERK1/2 in TMJOA. The effect of miR-21-5p on angiogenesis was evaluated by chick embryo chorioallantoic membrane (CAM) assay and WB. RESULTS:In the UAC model, the cartilage thickness and extracellular matrix of miR-21-5p knockout mice were less damaged, and miR-21-5p and UAC model were shown to affect the expression of Spry1, IL-1?, MMP-13, and VEGF. Luciferase experiments confirmed that Spry1 was the direct target of miR-21-5p. The expression levels of Spry1, MMP-13, VEGF and p-ERK1/2 in MCCs transfected with miR-21-5p mimic were higher than those in the inhibitor group. Under the simulated inflammatory environment of IL-1?, the expression levels of MMP-13, VEGF and p-ERK1/2 were positively correlated with miR-21-5p, while Spry1 was negatively correlated with miR-21-5p. Inhibition of miR-21-5p expression and overexpression of Spry1 enhanced the inhibition of MMP-13, VEGF and p-ERK1/2 expression. MiR-21-5p had a significant role in promoting angiogenesis in the chick embryo CAM assay, and this role was clearly mediated by the ERK-MAPK signalling pathway. CONCLUSION:This study verified that miR-21-5p can promote the process of TMJOA by targeting Spry1, which provides a new direction for future research on the treatment of this disease.

Dataset Information

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

Publications

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

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