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CCR4-Not
Multiprotein complex used in gene expression

Carbon Catabolite Repression 4—Negative On TATA-less, or CCR4-Not, is a multiprotein complex that functions in gene expression. The complex has multiple enzymatic activities as both a poly(A) 3′-5′ exonuclease and a ubiquitin ligase. The exonuclease activity of CCR4-Not shortens the poly(A) tail found at 3' end of almost every eukaryotic mRNA. The complex is present both in the nucleus where it regulates transcription and in the cytoplasm where it associates with translating ribosomes and RNA processing bodies. In mammalian cell, it has a function in the regulation of the cell cycle, chromatin modification, activation and inhibition of transcription initiation, control of transcription elongation, RNA export, nuclear RNA surveillance, and DNA damage repair in nucleus. Ccr4–Not complex plays an important role in mRNA decay and protein quality control in the cytoplasm.

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Subunits

The human CCR4-Not complex is composed of structural (non-catalytic) subunits and those that have exonuclease and E3 ligase activity. Some but not all of the human subunits are conserved in budding yeast.11 In yeast the complex has nine core subunits, comprising Ccr4 (carbon catabolite repression), Caf proteins (Ccr4 associated factor) (Caf1, Caf40, Caf130) and Not proteins (Not1, Not2, Not3, Not4, and Not5).12

SubunitMW (kDa)[A]Key Features
CNOT1267"Scaffold" with non-catalytic function. Linked to the maintenance of embryonic stem cells.13
CNOT260Structural component. Linked to the maintenance of embryonic stem cells.14
CNOT382Structural component. Linked to the maintenance of embryonic stem cells.1516
CNOT464Active as E3 ubiquitin ligase.17
CNOT6633′-5′ exonuclease with preference for polyadenylated mRNA substates.18 Has a human paralog CNOT6L.
CNOT7333′-5′ exonuclease that is partially redundant with CNOT8.19
CNOT8343′-5′ exonuclease.20
CNOT934Serves a non-catalytic function.21
CNOT1082Non-catalytic subunit that forms a module with CNOT11 that is absent in fungi.22
CNOT1155Non-catalytic subunit that forms a module with CNOT10 that is absent in fungi.23

A Molecular weight of human subunits from Uniprot.

See also

References

  1. Collart, Martine A. (2016-01-29). "The Ccr4-Not complex is a key regulator of eukaryotic gene expression". Wiley Interdisciplinary Reviews: RNA. 7 (4). Wiley: 438–454. doi:10.1002/wrna.1332. ISSN 1757-7004. PMC 5066686. PMID 26821858. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066686 ↩

  2. Miller, Jason E.; Reese, Joseph C. (2012-03-15). "Ccr4-Not complex: the control freak of eukaryotic cells". Critical Reviews in Biochemistry and Molecular Biology. 47 (4). Informa UK Limited: 315–333. doi:10.3109/10409238.2012.667214. ISSN 1040-9238. PMC 3376659. PMID 22416820. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376659 ↩

  3. Aslam, Akhmed; Mittal, Saloni; Koch, Frederic; Andrau, Jean-Christophe; Winkler, G. Sebastiaan (2009). Wickens, Marvin (ed.). "The Ccr4–Not Deadenylase Subunits CNOT7 and CNOT8 Have Overlapping Roles and Modulate Cell Proliferation". Molecular Biology of the Cell. 20 (17). American Society for Cell Biology (ASCB): 3840–3850. doi:10.1091/mbc.e09-02-0146. ISSN 1059-1524. PMC 2735483. PMID 19605561. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735483 ↩

  4. Chen J, Chiang YC, Denis CL (Mar 2002). "CCR4, a 3′-5′ poly(A) RNA and ssDNA exonuclease, is the catalytic component of the cytoplasmic deadenylase". EMBO J. 21 (6): 1414–26. doi:10.1093/emboj/21.6.1414. PMC 125924. PMID 11889047. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC125924 ↩

  5. "Entrez Gene: CNOT6 CCR4-NOT transcription complex, subunit 6". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=57472 ↩

  6. Albert, Thomas K.; Hanzawa, Hiroyuki; Legtenberg, Yvonne I.A.; de Ruwe, Marjolein J.; van den Heuvel, Fiona A.J.; Collart, Martine A.; Boelens, Rolf; Timmers, H.Th.Marc (2002-02-01). "Identification of a ubiquitin-protein ligase subunit within the CCR4-NOT transcription repressor complex". The EMBO Journal. 21 (3). Wiley: 355–364. doi:10.1093/emboj/21.3.355. ISSN 0261-4189. PMC 125831. PMID 11823428. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC125831 ↩

  7. Stowell, James A. W.; Webster, Michael W.; Kögel, Alexander; Wolf, Jana; Shelley, Kathryn L.; Passmore, Lori A. (2016-11-15). "Reconstitution of Targeted Deadenylation by the Ccr4-Not Complex and the YTH Domain Protein Mmi1". Cell Reports. 17 (8): 1978–1989. doi:10.1016/j.celrep.2016.10.066. ISSN 2211-1247. PMC 5120349. PMID 27851962. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120349 ↩

  8. Collart, Martine A. (2016-01-29). "The Ccr4-Not complex is a key regulator of eukaryotic gene expression". Wiley Interdisciplinary Reviews: RNA. 7 (4). Wiley: 438–454. doi:10.1002/wrna.1332. ISSN 1757-7004. PMC 5066686. PMID 26821858. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066686 ↩

  9. Miller, Jason E.; Reese, Joseph C. (2012-03-15). "Ccr4-Not complex: the control freak of eukaryotic cells". Critical Reviews in Biochemistry and Molecular Biology. 47 (4). Informa UK Limited: 315–333. doi:10.3109/10409238.2012.667214. ISSN 1040-9238. PMC 3376659. PMID 22416820. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376659 ↩

  10. Chalabi Hagkarim, Nafiseh; Grand, Roger J. (2020-10-29). "The Regulatory Properties of the Ccr4–Not Complex". Cells. 9 (11): 2379. doi:10.3390/cells9112379. ISSN 2073-4409. PMC 7692201. PMID 33138308. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692201 ↩

  11. Albert, T. K. (2000-02-01). "Isolation and characterization of human orthologs of yeast CCR4-NOT complex subunits". Nucleic Acids Research. 28 (3). Oxford University Press (OUP): 809–817. doi:10.1093/nar/28.3.809. ISSN 1362-4962. PMC 102560. PMID 10637334. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC102560 ↩

  12. Collart, Martine A (2003-08-14). "Global control of gene expression in yeast by the Ccr4-Not complex". Gene. 313: 1–16. doi:10.1016/S0378-1119(03)00672-3. ISSN 0378-1119. PMID 12957374. https://www.sciencedirect.com/science/article/pii/S0378111903006723 ↩

  13. Zheng, Xiaofeng; Dumitru, Raluca; Lackford, Brad L.; Freudenberg, Johannes M.; Singh, Ajeet P.; Archer, Trevor K.; Jothi, Raja; Hu, Guang (2012-04-09). "Cnot1, Cnot2, and Cnot3 Maintain Mouse and Human ESC Identity and Inhibit Extraembryonic Differentiation". Stem Cells. 30 (5). Wiley: 910–922. doi:10.1002/stem.1070. ISSN 1066-5099. PMC 3787717. PMID 22367759. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787717 ↩

  14. Zheng, Xiaofeng; Dumitru, Raluca; Lackford, Brad L.; Freudenberg, Johannes M.; Singh, Ajeet P.; Archer, Trevor K.; Jothi, Raja; Hu, Guang (2012-04-09). "Cnot1, Cnot2, and Cnot3 Maintain Mouse and Human ESC Identity and Inhibit Extraembryonic Differentiation". Stem Cells. 30 (5). Wiley: 910–922. doi:10.1002/stem.1070. ISSN 1066-5099. PMC 3787717. PMID 22367759. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787717 ↩

  15. Hu, G.; Kim, J.; Xu, Q.; Leng, Y.; Orkin, S. H.; Elledge, S. J. (2009-04-01). "A genome-wide RNAi screen identifies a new transcriptional module required for self-renewal". Genes & Development. 23 (7). Cold Spring Harbor Laboratory: 837–848. doi:10.1101/gad.1769609. ISSN 0890-9369. PMC 2666338. PMID 19339689. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2666338 ↩

  16. Zheng, Xiaofeng; Dumitru, Raluca; Lackford, Brad L.; Freudenberg, Johannes M.; Singh, Ajeet P.; Archer, Trevor K.; Jothi, Raja; Hu, Guang (2012-04-09). "Cnot1, Cnot2, and Cnot3 Maintain Mouse and Human ESC Identity and Inhibit Extraembryonic Differentiation". Stem Cells. 30 (5). Wiley: 910–922. doi:10.1002/stem.1070. ISSN 1066-5099. PMC 3787717. PMID 22367759. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787717 ↩

  17. Albert, Thomas K.; Hanzawa, Hiroyuki; Legtenberg, Yvonne I.A.; de Ruwe, Marjolein J.; van den Heuvel, Fiona A.J.; Collart, Martine A.; Boelens, Rolf; Timmers, H.Th.Marc (2002-02-01). "Identification of a ubiquitin-protein ligase subunit within the CCR4-NOT transcription repressor complex". The EMBO Journal. 21 (3). Wiley: 355–364. doi:10.1093/emboj/21.3.355. ISSN 0261-4189. PMC 125831. PMID 11823428. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC125831 ↩

  18. Chen J, Chiang YC, Denis CL (Mar 2002). "CCR4, a 3′-5′ poly(A) RNA and ssDNA exonuclease, is the catalytic component of the cytoplasmic deadenylase". EMBO J. 21 (6): 1414–26. doi:10.1093/emboj/21.6.1414. PMC 125924. PMID 11889047. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC125924 ↩

  19. Aslam, Akhmed; Mittal, Saloni; Koch, Frederic; Andrau, Jean-Christophe; Winkler, G. Sebastiaan (2009). Wickens, Marvin (ed.). "The Ccr4–Not Deadenylase Subunits CNOT7 and CNOT8 Have Overlapping Roles and Modulate Cell Proliferation". Molecular Biology of the Cell. 20 (17). American Society for Cell Biology (ASCB): 3840–3850. doi:10.1091/mbc.e09-02-0146. ISSN 1059-1524. PMC 2735483. PMID 19605561. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735483 ↩

  20. Aslam, Akhmed; Mittal, Saloni; Koch, Frederic; Andrau, Jean-Christophe; Winkler, G. Sebastiaan (2009). Wickens, Marvin (ed.). "The Ccr4–Not Deadenylase Subunits CNOT7 and CNOT8 Have Overlapping Roles and Modulate Cell Proliferation". Molecular Biology of the Cell. 20 (17). American Society for Cell Biology (ASCB): 3840–3850. doi:10.1091/mbc.e09-02-0146. ISSN 1059-1524. PMC 2735483. PMID 19605561. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735483 ↩

  21. Pavanello, Lorenzo; Hall, Benjamin; Airhihen, Blessing; Winkler, Gerlof Sebastiaan (2018-11-09). "The central region of CNOT1 and CNOT9 stimulates deadenylation by the Ccr4–Not nuclease module". Biochemical Journal. 475 (21). Portland Press Ltd.: 3437–3450. doi:10.1042/bcj20180456. ISSN 0264-6021. PMID 30309886. S2CID 52962278. https://nottingham-repository.worktribe.com/1162954/1/ ↩

  22. Mauxion, Fabienne; Prève, Brigitte; Séraphin, Bertrand (2013). "C2ORF29/CNOT11 and CNOT10 form a new module of the CCR4-NOT complex". RNA Biology. 10 (2). Informa UK Limited: 267–276. doi:10.4161/rna.23065. ISSN 1547-6286. PMC 3594285. PMID 23232451. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594285 ↩

  23. Mauxion, Fabienne; Prève, Brigitte; Séraphin, Bertrand (2013). "C2ORF29/CNOT11 and CNOT10 form a new module of the CCR4-NOT complex". RNA Biology. 10 (2). Informa UK Limited: 267–276. doi:10.4161/rna.23065. ISSN 1547-6286. PMC 3594285. PMID 23232451. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594285 ↩