A Mechanism for microRNA Arm Switching Regulated by Uridylation

Haedong Kim; Jimi Kim; Sha Yu; Young Yoon Lee; Junseong Park; Ran Joo Choi; Seon Jin Yoon; Seok Gu Kang; V. Narry Kim

doi:10.1016/j.molcel.2020.04.030

A Mechanism for microRNA Arm Switching Regulated by Uridylation

Haedong Kim, Jimi Kim, Sha Yu, Young Yoon Lee, Junseong Park, Ran Joo Choi, Seon Jin Yoon, Seok Gu Kang, V. Narry Kim

Department of Neurosurgery

Research output: Contribution to journal › Article › peer-review

32 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1224-1236.e5
Journal	Molecular Cell
Volume	78
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2020.04.030
Publication status	Published - 2020 Jun 18

Bibliographical note

Funding 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.). Conceptualization, H.K. J.K. and V.N.K.; Methodology, H.K. J.K. S.Y. Y.-Y.L. and V.N.K.; Formal Analysis, H.K. J.P. R.J.C. and S.-J.Y.; Investigation, H.K. J.K. S.Y. Y.-Y.L. J.P. R.J.C. and S.-J.Y.; Resources, J.P. R.J.C. S.-J.Y. and S.-G.K.; Writing – Original Draft, H.K. J.K. S.Y. J.P. R.J.C. S.-J.Y. S.-G.K. and V.N.K.; Writing – Review & Editing, H.K. J.K. S.Y. Y.-Y.L. and V.N.K.; Visualization, H.K. J.K. and V.N.K.; Supervision, S.-G.K. and V.N.K.; Funding Acquisition, H.K. Y.-Y.L. and V.N.K. H.K. J.K. and V.N.K. have filed patent applications on this work.

Funding 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.).

Publisher Copyright:
© 2020 Elsevier Inc.

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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10.1016/j.molcel.2020.04.030

Cite this

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title = "A Mechanism for microRNA Arm Switching Regulated by Uridylation",

abstract = "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.",

author = "Haedong Kim and Jimi Kim and Sha Yu and Lee, {Young Yoon} and Junseong Park and Choi, {Ran Joo} and Yoon, {Seon Jin} and Kang, {Seok Gu} and Kim, {V. Narry}",

note = "Funding 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.). Conceptualization, H.K. J.K. and V.N.K.; Methodology, H.K. J.K. S.Y. Y.-Y.L. and V.N.K.; Formal Analysis, H.K. J.P. R.J.C. and S.-J.Y.; Investigation, H.K. J.K. S.Y. Y.-Y.L. J.P. R.J.C. and S.-J.Y.; Resources, J.P. R.J.C. S.-J.Y. and S.-G.K.; Writing – Original Draft, H.K. J.K. S.Y. J.P. R.J.C. S.-J.Y. S.-G.K. and V.N.K.; Writing – Review & Editing, H.K. J.K. S.Y. Y.-Y.L. and V.N.K.; Visualization, H.K. J.K. and V.N.K.; Supervision, S.-G.K. and V.N.K.; Funding Acquisition, H.K. Y.-Y.L. and V.N.K. H.K. J.K. and V.N.K. have filed patent applications on this work. Funding 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.). Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = jun,

day = "18",

doi = "10.1016/j.molcel.2020.04.030",

language = "English",

volume = "78",

pages = "1224--1236.e5",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - A Mechanism for microRNA Arm Switching Regulated by Uridylation

AU - Kim, Haedong

AU - Kim, Jimi

AU - Yu, Sha

AU - Lee, Young Yoon

AU - Park, Junseong

AU - Choi, Ran Joo

AU - Yoon, Seon Jin

AU - Kang, Seok Gu

AU - Kim, V. Narry

N1 - Funding 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.). Conceptualization, H.K. J.K. and V.N.K.; Methodology, H.K. J.K. S.Y. Y.-Y.L. and V.N.K.; Formal Analysis, H.K. J.P. R.J.C. and S.-J.Y.; Investigation, H.K. J.K. S.Y. Y.-Y.L. J.P. R.J.C. and S.-J.Y.; Resources, J.P. R.J.C. S.-J.Y. and S.-G.K.; Writing – Original Draft, H.K. J.K. S.Y. J.P. R.J.C. S.-J.Y. S.-G.K. and V.N.K.; Writing – Review & Editing, H.K. J.K. S.Y. Y.-Y.L. and V.N.K.; Visualization, H.K. J.K. and V.N.K.; Supervision, S.-G.K. and V.N.K.; Funding Acquisition, H.K. Y.-Y.L. and V.N.K. H.K. J.K. and V.N.K. have filed patent applications on this work. Funding 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.). Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/6/18

Y1 - 2020/6/18

N2 - 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.

AB - 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.

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A Mechanism for microRNA Arm Switching Regulated by Uridylation

Abstract

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