Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 31, Pages 11467-11472Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1317751111
Keywords
nucleotidyl transferase; microRNA processing
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Funding
- Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- Genome Network Project from MEXT
- Innovative Cell Biology by Innovative Technology (Cell Innovation Program) from MEXT
- MEXT
- Hendrik Muller Foundation (Netherlands)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health [U54HD007495]
- Japan Society for the Promotion of Science
- Grants-in-Aid for Scientific Research [23249040, 25670678] Funding Source: KAKEN
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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.
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