| Structural highlights
Disease
[CNOT3_HUMAN] Precursor T-cell acute lymphoblastic leukemia.
Function
[CNOT1_HUMAN] Belongs to the CCR4-NOT complex that functions as general transcription regulation complex. Acts as a transcriptional repressor. Represses the ligand-dependent transcriptional activation by nuclear receptors.[1] [2] [CNOT3_HUMAN] Component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. May be involved in metabolic regulation; may be involved in recruitment of the CCR4-NOT complex to deadenylation target mRNAs involved in energy metabolism. Involved in mitotic progression and regulation of the spindle assembly checkpoint by regulating the stability of MAD1L1 mRNA. Can repress transcription and may link the CCR4-NOT complex to transcriptional regulation; the repressive function may involve histone deacetylases. Involved in the maintenance of emryonic stem (ES) cell identity.[3] [4] [5] [CNOT2_HUMAN] Component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. Required for the CCR4-NOT complex structural integrity. Can repress transcription and may link the CCR4-NOT complex to transcriptional regulation; the repressive function may specificly involve the N-Cor repressor complex containing HDAC3, NCOR1 and NCOR2. Involved in the maintenance of emryonic stem (ES) cell identity.[6] [7] [8] [9]
Publication Abstract from PubMed
Nanos proteins repress the expression of target mRNAs by recruiting effector complexes through non-conserved N-terminal regions. In vertebrates, Nanos proteins interact with the NOT1 subunit of the CCR4-NOT effector complex through a NOT1 interacting motif (NIM), which is absent in Nanos orthologs from several invertebrate species. Therefore, it has remained unclear whether the Nanos repressive mechanism is conserved and whether it also involves direct interactions with the CCR4-NOT deadenylase complex in invertebrates. Here, we identify an effector domain (NED) that is necessary for the Drosophila melanogaster (Dm) Nanos to repress mRNA targets. The NED recruits the CCR4-NOT complex through multiple and redundant binding sites, including a central region that interacts with the NOT module, which comprises the C-terminal domains of NOT1-3. The crystal structure of the NED central region bound to the NOT module reveals an unanticipated bipartite binding interface that contacts NOT1 and NOT3 and is distinct from the NIM of vertebrate Nanos. Thus, despite the absence of sequence conservation, the N-terminal regions of Nanos proteins recruit CCR4-NOT to assemble analogous repressive complexes.
Distinct modes of recruitment of the CCR4-NOT complex by Drosophila and vertebrate Nanos.,Raisch T, Bhandari D, Sabath K, Helms S, Valkov E, Weichenrieder O, Izaurralde E EMBO J. 2016 May 2;35(9):974-90. doi: 10.15252/embj.201593634. Epub 2016 Mar 11. PMID:26968986[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Albert TK, Lemaire M, van Berkum NL, Gentz R, Collart MA, Timmers HT. Isolation and characterization of human orthologs of yeast CCR4-NOT complex subunits. Nucleic Acids Res. 2000 Feb 1;28(3):809-17. PMID:10637334
- ↑ Winkler GS, Mulder KW, Bardwell VJ, Kalkhoven E, Timmers HT. Human Ccr4-Not complex is a ligand-dependent repressor of nuclear receptor-mediated transcription. EMBO J. 2006 Jul 12;25(13):3089-99. Epub 2006 Jun 15. PMID:16778766 doi:7601194
- ↑ Zwartjes CG, Jayne S, van den Berg DL, Timmers HT. Repression of promoter activity by CNOT2, a subunit of the transcription regulatory Ccr4-not complex. J Biol Chem. 2004 Mar 19;279(12):10848-54. Epub 2004 Jan 5. PMID:14707134 doi:http://dx.doi.org/10.1074/jbc.M311747200
- ↑ Takahashi A, Kikuguchi C, Morita M, Shimodaira T, Tokai-Nishizumi N, Yokoyama K, Ohsugi M, Suzuki T, Yamamoto T. Involvement of CNOT3 in mitotic progression through inhibition of MAD1 expression. Biochem Biophys Res Commun. 2012 Mar 9;419(2):268-73. doi:, 10.1016/j.bbrc.2012.02.007. Epub 2012 Feb 10. PMID:22342980 doi:http://dx.doi.org/10.1016/j.bbrc.2012.02.007
- ↑ Zheng X, Dumitru R, Lackford BL, Freudenberg JM, Singh AP, Archer TK, Jothi R, Hu G. Cnot1, Cnot2, and Cnot3 maintain mouse and human ESC identity and inhibit extraembryonic differentiation. Stem Cells. 2012 May;30(5):910-22. doi: 10.1002/stem.1070. PMID:22367759 doi:http://dx.doi.org/10.1002/stem.1070
- ↑ Zwartjes CG, Jayne S, van den Berg DL, Timmers HT. Repression of promoter activity by CNOT2, a subunit of the transcription regulatory Ccr4-not complex. J Biol Chem. 2004 Mar 19;279(12):10848-54. Epub 2004 Jan 5. PMID:14707134 doi:http://dx.doi.org/10.1074/jbc.M311747200
- ↑ Jayne S, Zwartjes CG, van Schaik FM, Timmers HT. Involvement of the SMRT/NCoR-HDAC3 complex in transcriptional repression by the CNOT2 subunit of the human Ccr4-Not complex. Biochem J. 2006 Sep 15;398(3):461-7. PMID:16712523 doi:http://dx.doi.org/10.1042/BJ20060406
- ↑ Ito K, Inoue T, Yokoyama K, Morita M, Suzuki T, Yamamoto T. CNOT2 depletion disrupts and inhibits the CCR4-NOT deadenylase complex and induces apoptotic cell death. Genes Cells. 2011 Apr;16(4):368-79. doi: 10.1111/j.1365-2443.2011.01492.x. Epub, 2011 Feb 8. PMID:21299754 doi:http://dx.doi.org/10.1111/j.1365-2443.2011.01492.x
- ↑ Zheng X, Dumitru R, Lackford BL, Freudenberg JM, Singh AP, Archer TK, Jothi R, Hu G. Cnot1, Cnot2, and Cnot3 maintain mouse and human ESC identity and inhibit extraembryonic differentiation. Stem Cells. 2012 May;30(5):910-22. doi: 10.1002/stem.1070. PMID:22367759 doi:http://dx.doi.org/10.1002/stem.1070
- ↑ Raisch T, Bhandari D, Sabath K, Helms S, Valkov E, Weichenrieder O, Izaurralde E. Distinct modes of recruitment of the CCR4-NOT complex by Drosophila and vertebrate Nanos. EMBO J. 2016 May 2;35(9):974-90. doi: 10.15252/embj.201593634. Epub 2016 Mar 11. PMID:26968986 doi:http://dx.doi.org/10.15252/embj.201593634
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