Advanced

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

Boele, Joost; Persson, Helena LU ; Shin, Jay W; Ishizu, Yuri; Newie, Inga LU ; Sökilde, Rolf LU ; Hawkins, Shannon M; Coarfa, Cristian; Ikeda, Kazuhiro and Takayama, Ken-Ichi, et al. (2014) In Proceedings of the National Academy of Sciences 111(31). p.11467-11472
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'... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
111
issue
31
pages
11467 - 11472
publisher
National Acad Sciences
external identifiers
  • pmid:25049417
  • wos:000339807200052
  • scopus:84905656796
ISSN
1091-6490
DOI
10.1073/pnas.1317751111
language
English
LU publication?
yes
id
744edfd6-bc20-4621-aa08-c8d39cd0195f (old id 4581493)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25049417?dopt=Abstract
date added to LUP
2014-08-09 14:33:18
date last changed
2017-11-19 03:21:11
@article{744edfd6-bc20-4621-aa08-c8d39cd0195f,
  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.},
  author       = {Boele, Joost and Persson, Helena and Shin, Jay W and Ishizu, Yuri and Newie, Inga and Sökilde, Rolf and Hawkins, Shannon M and Coarfa, Cristian and Ikeda, Kazuhiro and Takayama, Ken-Ichi and Horie-Inoue, Kuniko and Ando, Yoshinari and Burroughs, A Maxwell and Sasaki, Chihiro and Suzuki, Chizuru and Sakai, Mizuho and Aoki, Shintaro and Ogawa, Ayumi and Hasegawa, Akira and Lizio, Marina and Kaida, Kaoru and Teusink, Bas and Carninci, Piero and Suzuki, Harukazu and Inoue, Satoshi and Gunaratne, Preethi H and Rovira, Carlos and Hayashizaki, Yoshihide and de Hoon, Michiel J L},
  issn         = {1091-6490},
  language     = {eng},
  number       = {31},
  pages        = {11467--11472},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {PAPD5-mediated 3' adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease.},
  url          = {http://dx.doi.org/10.1073/pnas.1317751111},
  volume       = {111},
  year         = {2014},
}