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The CCR4–NOT complex maintains liver homeostasis through mRNA deadenylation

Akinori Takahashi, View ORCID ProfileToru Suzuki  Correspondence email, View ORCID ProfileShou Soeda, View ORCID ProfileShohei Takaoka, Shungo Kobori, View ORCID ProfileTomokazu Yamaguchi, View ORCID ProfileHaytham Mohamed Aly Mohamed, View ORCID ProfileAkiko Yanagiya, Takaya Abe, Mayo Shigeta, Yasuhide Furuta, View ORCID ProfileKeiji Kuba, View ORCID ProfileTadashi Yamamoto  Correspondence email
Akinori Takahashi
1Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
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Toru Suzuki
5Laboratory for Immunogenetics, Center for Integrative Medical Sciences, RIKEN, Yokohama City, Kanagawa, Japan
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  • ORCID record for Toru Suzuki
  • For correspondence: toru.suzuki.ff@riken.jp
Shou Soeda
1Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
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  • ORCID record for Shou Soeda
Shohei Takaoka
1Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
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  • ORCID record for Shohei Takaoka
Shungo Kobori
2Nucleic Acid Chemistry and Engineering Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
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Tomokazu Yamaguchi
3Department of Biochemistry and Metabolic Science, Graduate School of Medicine, Akita University, Akita, Japan
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  • ORCID record for Tomokazu Yamaguchi
Haytham Mohamed Aly Mohamed
1Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
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  • ORCID record for Haytham Mohamed Aly Mohamed
Akiko Yanagiya
1Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
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  • ORCID record for Akiko Yanagiya
Takaya Abe
4Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
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Mayo Shigeta
4Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
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Yasuhide Furuta
4Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
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Keiji Kuba
3Department of Biochemistry and Metabolic Science, Graduate School of Medicine, Akita University, Akita, Japan
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  • ORCID record for Keiji Kuba
Tadashi Yamamoto
1Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan
5Laboratory for Immunogenetics, Center for Integrative Medical Sciences, RIKEN, Yokohama City, Kanagawa, Japan
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  • ORCID record for Tadashi Yamamoto
  • For correspondence: tadashi.yamamoto@oist.jp
Published 1 April 2020. DOI: 10.26508/lsa.201900494
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Abstract

The biological significance of deadenylation in global gene expression is not fully understood. Here, we show that the CCR4–NOT deadenylase complex maintains expression of mRNAs, such as those encoding transcription factors, cell cycle regulators, DNA damage response–related proteins, and metabolic enzymes, at appropriate levels in the liver. Liver-specific disruption of Cnot1, encoding a scaffold subunit of the CCR4–NOT complex, leads to increased levels of mRNAs for transcription factors, cell cycle regulators, and DNA damage response–related proteins because of reduced deadenylation and stabilization of these mRNAs. CNOT1 suppression also results in an increase of immature, unspliced mRNAs (pre-mRNAs) for apoptosis-related and inflammation-related genes and promotes RNA polymerase II loading on their promoter regions. In contrast, mRNAs encoding metabolic enzymes become less abundant, concomitant with decreased levels of these pre-mRNAs. Lethal hepatitis develops concomitantly with abnormal mRNA expression. Mechanistically, the CCR4–NOT complex targets and destabilizes mRNAs mainly through its association with Argonaute 2 (AGO2) and butyrate response factor 1 (BRF1) in the liver. Therefore, the CCR4–NOT complex contributes to liver homeostasis by modulating the liver transcriptome through mRNA deadenylation.

  • Received July 19, 2019.
  • Revision received March 11, 2020.
  • Accepted March 14, 2020.
  • © 2020 Takahashi et al.
Creative Commons logoCreative Commons logohttps://creativecommons.org/licenses/by/4.0/

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

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The CCR4–NOT complex maintains liver homeostasis
Akinori Takahashi, Toru Suzuki, Shou Soeda, Shohei Takaoka, Shungo Kobori, Tomokazu Yamaguchi, Haytham Mohamed Aly Mohamed, Akiko Yanagiya, Takaya Abe, Mayo Shigeta, Yasuhide Furuta, Keiji Kuba, Tadashi Yamamoto
Life Science Alliance Apr 2020, 3 (5) e201900494; DOI: 10.26508/lsa.201900494

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The CCR4–NOT complex maintains liver homeostasis
Akinori Takahashi, Toru Suzuki, Shou Soeda, Shohei Takaoka, Shungo Kobori, Tomokazu Yamaguchi, Haytham Mohamed Aly Mohamed, Akiko Yanagiya, Takaya Abe, Mayo Shigeta, Yasuhide Furuta, Keiji Kuba, Tadashi Yamamoto
Life Science Alliance Apr 2020, 3 (5) e201900494; DOI: 10.26508/lsa.201900494
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Volume 3, No. 5
May 2020
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