RT Journal Article
SR Electronic
T1 The CCR4–NOT complex maintains liver homeostasis through mRNA deadenylation
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900494
DO 10.26508/lsa.201900494
VO 3
IS 5
A1 Takahashi, Akinori
A1 Suzuki, Toru
A1 Soeda, Shou
A1 Takaoka, Shohei
A1 Kobori, Shungo
A1 Yamaguchi, Tomokazu
A1 Mohamed, Haytham Mohamed Aly
A1 Yanagiya, Akiko
A1 Abe, Takaya
A1 Shigeta, Mayo
A1 Furuta, Yasuhide
A1 Kuba, Keiji
A1 Yamamoto, Tadashi
YR 2020
UL http://www.life-science-alliance.org/content/3/5/e201900494.abstract
AB 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.