title: CNOT2 depletion disrupts and inhibits the CCR4-NOT deadenylase complex and induces apoptotic cell death.
abstract: Eukaryotic mRNA decay is initiated by shortening of the poly (A) tail; however, neither the molecular mechanisms underlying deadenylation nor its regulation is well understood. The human CCR4-NOT complex is a major cytoplasmic deadenylase consisting of a combination of at least nine subunits, four of which have deadenylase activity. The roles of the other subunits remain obscure. Here, we show that CNOT2 depletion by siRNA induces apoptosis. We also show that CNOT2 depletion destabilizes the complex, resulting in the formation of a complex smaller than that formed in control siRNA-treated cells. The deadenylase activity of the CNOT6L subunit-containing complex prepared from CNOT2-depleted cells was less than that from control cells. Intriguingly, the formation of P-bodies, where mRNA degradation supposedly takes place, was largely suppressed in CNOT2-depleted cells. Furthermore, CNOT2 depletion enhanced CHOP mRNA levels, suggesting that endoplasmic reticulum (ER) stress was occurring, which causes apoptosis in a caspase-dependent manner. These results suggest that CNOT2 is important for controlling cell viability through the maintenance of the structural integrity and enzymatic activity of the CCR4-NOT complex.
authors.affiliation: Division of Oncology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ito
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inoue
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Masahiro
authors.initials: M
authors.lastname: Morita
authors.forename: Toru
authors.initials: T
authors.lastname: Suzuki
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D017209:Apoptosis / Q000502:physiology; D005095:Exoribonucleases / Q000378:metabolism*; D006801:Humans; D021122:Protein Subunits; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: D005095:Exoribonucleases; D021122:Protein Subunits; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C485365:CNOT2 protein, human; C534418:cNOT6 protein, human