The CCR4-NOT complex maintains liver homeostasis through mRNA deadenylation

Life Sci Alliance. 2020 Apr 1;3(5):e201900494. doi: 10.26508/lsa.201900494. Print 2020 May.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytoplasm / metabolism
  • Female
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Homeostasis
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Poly A / genetics
  • RNA Stability
  • RNA, Messenger / genetics
  • Receptors, CCR4 / genetics
  • Receptors, CCR4 / metabolism*
  • Ribonucleases / genetics
  • TATA-Binding Protein Associated Factors / metabolism
  • Transcription Factors / genetics


  • Ccr4 protein, mouse
  • Homeodomain Proteins
  • Not protein, mouse
  • RNA, Messenger
  • Receptors, CCR4
  • TATA-Binding Protein Associated Factors
  • Transcription Factors
  • Poly A
  • Ribonucleases