Strand selection is a critical step in microRNA (miRNA) biogenesis. Although the dominant strand may change depending on cellular contexts, the molecular mechanism and physiological significance of such alternative strand selection (or “arm switching”) remain elusive. Here we find miR-324 to be one of the strongly regulated miRNAs by arm switching and identify the terminal uridylyl transferases TUT4 and TUT7 to be the key regulators. Uridylation of pre-miR-324 by TUT4/7 re-positions DICER on the pre-miRNA and shifts the cleavage site. This alternative processing produces a duplex with a different terminus from which the 3′ strand (3p) is selected instead of the 5′ strand (5p). In glioblastoma, the TUT4/7 and 3p levels are upregulated, whereas the 5p level is reduced. Manipulation of the strand ratio is sufficient to impair glioblastoma cell proliferation. This study uncovers a role of uridylation as a molecular switch in alternative strand selection and implicates its therapeutic potential. Alternative strand selection (or “arm switching”) of miRNAs takes place depending on cellular context, but its molecular mechanism is unknown. Kim et al. identify miR-324 as one of the prominently regulated miRNAs by arm switching and reveal the mechanism involving uridylation.
Bibliographical noteFunding Information:
We are grateful to Eunji Kim for cloning and mutagenesis of expression constructs. We also thank Yoonseok Jung, Dongwan Kim, Hyunjoon Kim, Kijun Kim, Myeonghwan Kim, Sung-Chul Kwon, Yongwoo Na, Jae Ho Paek, Soomin Son, Buyeon Um, Hyerim Yi, and other members of our laboratory for helpful discussions. The survival analysis result is based on data generated by the TCGA Research Network ( https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga ). This research was supported by the Institute for Basic Science from the Ministry of Science and ICT of Korea ( IBS-R008-D1 to H.K., J.K., S.Y., Y.-Y.L., and V.N.K.), BK21 research fellowships from the Ministry of Education of Korea (to H.K. and Y.-Y.L.), and an NRF (National Research Foundation of Korea) grant funded by the Korean government ( NRF-2015-Global Ph.D. Fellowship Program to H.K. and NRF-2018-Global Ph.D. Fellowship Program to Y.-Y.L.).
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology