Abstract
The CCR4-NOT complex is a highly conserved, multifunctional machinery controlling mRNA metabolism. Its components have been implicated in several aspects of mRNA and protein expression, including transcription initiation, elongation, mRNA degradation, ubiquitination, and protein modification. In this review, we will focus on the role of the CCR4-NOT complex in mRNA degradation. The complex contains two types of deadenylase enzymes, one belonging to the DEDD-type family and one belonging to the EEP-type family, which shorten the poly(A) tails of mRNA. We will review the present state of structure-function analyses into the CCR4-NOT deadenylases and summarize current understanding of their roles in mRNA degradation. We will also review structural and functional work on the Tob/BTG family of proteins, which are known to interact with the CCR4-NOT complex and which have been reported to suppress deadenylase activity in vitro.
Contributor Information
Mark Bartlam, Email: bartlam@nankai.edu.cn.
Tadashi Yamamoto, Email: tyamamot@ims.u-tokyo.ac.jp.
References
- Albert T.K., Lemaire M., van Berkum N.L., Gentz R., Collart M.A., Timmers H.T. Isolation and characterization of human orthologs of yeast CCR4-NOT complex subunits. Nucleic Acids Res. 2000;28:809–817. doi: 10.1093/nar/28.3.809. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Albert T.K., Hanzawa H., Legtenberg Y.I., de Ruwe M.J., van den Heuvel F.A., Collart M.A., Boelens R., Timmers H.T. Identification of a ubiquitin-protein ligase subunit within the CCR4-NOT transcription repressor complex. EMBO J. 2002;21:355–364. doi: 10.1093/emboj/21.3.355. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Andersen K.R., Jonstrup A.T., Van L.B., Brodersen D.E. The activity and selectivity of fission yeast Pop2p are affected by a high affinity for Zn2+ and Mn2+ in the active site. RNA. 2009;15:850–861. doi: 10.1261/rna.1489409. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Badarinarayana V., Chiang Y.C., Denis C.L. Functional interaction of CCR4-NOT proteins with TATAA-binding protein (TBP) and its associated factors in yeast. Genetics. 2000;155:1045–1054. doi: 10.1093/genetics/155.3.1045. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bai Y., Salvadore C., Chiang Y.C., Collart M.A., Liu H.Y., Denis C.L. The CCR4 and CAF1 proteins of the CCR4-NOT complex are physically and functionally separated from NOT2, NOT4, and NOT5. Mol Cell Biol. 1999;19:6642–6651. doi: 10.1128/MCB.19.10.6642. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Benson J.D., Benson M., Howley P.M., Struhl K. Association of distinct yeast Not2 functional domains with components of Gcn5 histone acetylase and Ccr4 transcriptional regulatory complexes. EMBO J. 1998;17:6714–6722. doi: 10.1093/emboj/17.22.6714. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Berthet C., Guéhenneux F., Revol V., Samarut C., Lukaszewicz A., Dehay C., Dumontet C., Magaud J.P., Rouault J.P. Interaction of PRMT1 with BTG/TOB proteins in cell signalling: molecular analysis and functional aspects. Genes Cells. 2002;7:29–39. doi: 10.1046/j.1356-9597.2001.00497.x. [DOI] [PubMed] [Google Scholar]
- Berthet C., Morera A.M., Asensio M.J., Chauvin M.A., Morel A.P., Dijoud F., Magaud J.P., Durand P., Rouault J.P. CCR4-associated factor CAF1 is an essential factor for spermatogenesis. Mol Cell Biol. 2004;24:5808–5820. doi: 10.1128/MCB.24.13.5808-5820.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bogdan J.A., Adams-Burton C., Pedicord D.L., Sukovich D.A., Benfield P.A., Corjay M.H., Stoltenborg J.K., Dicker I.B. Human carbon catabolite repressor protein (CCR4)-associative factor 1: cloning, expression and characterization of its interaction with the B-cell translocation protein BTG1. Biochem J. 1998;336:471–481. doi: 10.1042/bj3360471. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chen J., Rappsilber J., Chiang Y.C., Russell P., Mann M., Denis C.L. Purification and characterization of the 1.0 MDa CCR4-NOT complex identifies two novel components of the complex. J Mol Biol. 2001;314:683–694. doi: 10.1006/jmbi.2001.5162. [DOI] [PubMed] [Google Scholar]
- Chen J., Chiang Y.C., Denis C.L. CCR4, a 3–5 poly(A) RNA and ssDNA exonuclease, is the catalytic component of the cytoplasmic deadenylase. EMBO J. 2002;21:1414–1426. doi: 10.1093/emboj/21.6.1414. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Collart M.A. Global control of gene expression in yeast by the Ccr4-Not complex. Gene. 2003;313:1–16. doi: 10.1016/S0378-1119(03)00672-3. [DOI] [PubMed] [Google Scholar]
- Collart M.A., Struhl K. CDC39, an essential nuclear protein that negatively regulates transcription and differentially affects the constitutive and inducible HIS3 promoters. EMBO J. 1993;12:177–186. doi: 10.1002/j.1460-2075.1993.tb05643.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Collart M.A., Struhl K. NOT1(CDC39), NOT2(CDC36), NOT3, and NOT4 encode a global-negative regulator of transcription that differentially affects TATA-element utilization. Genes Dev. 1994;8:525–537. doi: 10.1101/gad.8.5.525. [DOI] [PubMed] [Google Scholar]
- Collart M.A., Timmers H.T. The eukaryotic Ccr4-not complex: a regulatory platform integrating mRNA metabolism with cellular signaling pathways? Prog Nucleic Acid Res Mol Biol. 2004;77:289–322. doi: 10.1016/S0079-6603(04)77008-7. [DOI] [PubMed] [Google Scholar]
- Cui Y., Ramnarain D.B., Chiang Y.C., Ding L.H., McMahon J.S., Denis C.L. Genome wide expression analysis of the CCR4-NOT complex indicates that it consists of three modules with the NOT module controlling SAGA-responsive genes. Mol Genet Genomics. 2008;279:323–337. doi: 10.1007/s00438-007-0314-1. [DOI] [PubMed] [Google Scholar]
- Deluen C., James N., Maillet L., Molinete M., Theiler G., Lemaire M., Paquet N., Collart M.A. The Ccr4-not complex and yTAF1 (yTaf(II)130p/yTaf(II)145p) show physical and functional interactions. Mol Cell Biol. 2002;22:6735–6749. doi: 10.1128/MCB.22.19.6735-6749.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Denis C.L., Chen J. The CCR4-NOT complex plays diverse roles in mRNA metabolism. Prog Nucleic Acid Res Mol Biol. 2003;73:221–250. doi: 10.1016/S0079-6603(03)01007-9. [DOI] [PubMed] [Google Scholar]
- Dlakić M. Functionally unrelated signalling proteins contain a fold similar to Mg2+-dependent endonucleases. Trends Biochem Sci. 2000;25:272–273. doi: 10.1016/S0968-0004(00)01582-6. [DOI] [PubMed] [Google Scholar]
- Doma M.K., Parker R. RNA quality control in eukaryotes. Cell. 2007;131:660–668. doi: 10.1016/j.cell.2007.10.041. [DOI] [PubMed] [Google Scholar]
- Draper M.P., Liu H.Y., Nelsbach A.H., Mosley S.P., Denis C.L. CCR4 is a glucose-regulated transcription factor whose leucine-rich repeat binds several proteins important for placing CCR4 in its proper promoter context. Mol Cell Biol. 1994;14:4522–4531. doi: 10.1128/MCB.14.7.4522. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Draper M.P., Salvadore C., Denis C.L. Identification of a mouse protein whose homolog in Saccharomyces cerevisiae is a component of the CCR4 transcriptional regulatory complex. Mol Cell Biol. 1995;15:3487–3495. doi: 10.1128/MCB.15.7.3487. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dupressoir A., Morel A.P., Barbot W., Loireau M.P., Corbo L., Heidmann T. Identification of four families of yCCR4- and Mg2+-dependent endonuclease-related proteins in higher eukaryotes, and characterization of orthologs of yCCR4 with a conserved leucine-rich repeat essential for hCAF1/hPOP2 binding. BMC Genomics. 2001;2:9. doi: 10.1186/1471-2164-2-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gavin A.C., Bösche M., Krause R., Grandi P., Marzioch M., Bauer A., Schultz J., Rick J.M., Michon A.M., Cruciat C.M., et al. Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature. 2002;415:141–147. doi: 10.1038/415141a. [DOI] [PubMed] [Google Scholar]
- Goldstrohm A.C., Wickens M. Multifunctional deadenylase complexes diversify mRNA control. Nat Rev Mol Cell Biol. 2008;9:337–344. doi: 10.1038/nrm2370. [DOI] [PubMed] [Google Scholar]
- Guéhenneux F., Duret L., Callanan M.B., Bouhas R., Hayette S., Berthet C., Samarut C., Rimokh R., Birot A.M., Wang Q., et al. Cloning of the mouse BTG3 gene and definition of a new gene family (the BTG family) involved in the negative control of the cell cycle. Leukemia. 1997;11:370–375. doi: 10.1038/sj.leu.2400599. [DOI] [PubMed] [Google Scholar]
- Hanzawa H., de Ruwe M.J., Albert T.K., van Der Vliet P.C., Timmers H.T., Boelens R. The structure of the C4C4 ring finger of human NOT4 reveals features distinct from those of C3HC4 RING fingers. J Biol Chem. 2001;276:10185–10190. doi: 10.1074/jbc.M009298200. [DOI] [PubMed] [Google Scholar]
- Hata H., Mitsui H., Liu H., Bai Y., Denis C.L., Shimizu Y., Sakai A. Dhh1p, a putative RNA helicase, associates with the general transcription factors Pop2p and Ccr4p from Saccharomyces cerevisiae. Genetics. 1998;148:571–579. doi: 10.1093/genetics/148.2.571. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Horiuchi M., Takeuchi K., Noda N., Muroya N., Suzuki T., Nakamura T., Kawamura-Tsuzuku J., Takahasi K., Yamamoto T., Inagaki F. Structural basis for the antiproliferative activity of the Tob-hCaf1 complex. J Biol Chem. 2009;284:13244–13255. doi: 10.1074/jbc.M809250200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Komarnitsky S.I., Chiang Y.C., Luca F.C., Chen J., Toyn J.H., Winey M., Johnston L.H., Denis C.L. DBF2 protein kinase binds to and acts through the cell cycle-regulated MOB1 protein. Mol Cell Biol. 1998;18:2100–2107. doi: 10.1128/MCB.18.4.2100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lau N.C., Kolkman A., van Schaik F.M., Mulder K.W., Pijnappel W. W., Heck A.J., Timmers H.T. Human Ccr4-Not complexes contain variable deadenylase subunits. Biochem J. 2009;422:443–453. doi: 10.1042/BJ20090500. [DOI] [PubMed] [Google Scholar]
- Lee T.I., Wyrick J.J., Koh S.S., Jennings E.G., Gadbois E.L., Young R.A. Interplay of positive and negative regulators in transcription initiation by RNA polymerase II holoenzyme. Mol Cell Biol. 1998;18:4455–4462. doi: 10.1128/MCB.18.8.4455. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lenssen E., Oberholzer U., Labarre J., De Virgilio C., Collart M.A. Saccharomyces cerevisiae Ccr4-not complex contributes to the control of Msn2p-dependent transcription by the Ras/cAMP pathway. Mol Microbiol. 2002;43:1023–1037. doi: 10.1046/j.1365-2958.2002.02799.x. [DOI] [PubMed] [Google Scholar]
- Liu H.Y., Toyn J.H., Chiang Y.C., Draper M.P., Johnston L.H., Denis C.L. DBF2, a cell cycle-regulated protein kinase, is physically and functionally associated with the CCR4 transcriptional regulatory complex. EMBO J. 1997;16:5289–5298. doi: 10.1093/emboj/16.17.5289. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu H.Y., Badarinarayana V., Audino D.C., Rappsilber J., Mann M., Denis C.L. The NOT proteins are part of the CCR4 transcriptional complex and affect gene expression both positively and negatively. EMBO J. 1998;17:1096–1106. doi: 10.1093/emboj/17.4.1096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu H.Y., Chiang Y.C., Pan J., Chen J., Salvadore C., Audino D.C., Badarinarayana V., Palaniswamy V., Anderson B., Denis C. L. Characterization of CAF4 and CAF16 reveals a functional connection between the CCR4-NOT complex and a subset of SRB proteins of the RNA polymerase II holoenzyme. J Biol Chem. 2001;276:7541–7548. doi: 10.1074/jbc.M009112200. [DOI] [PubMed] [Google Scholar]
- Liu Q., Greimann J.C., Lima C.D. Reconstitution, activities, and structure of the eukaryotic RNA exosome. Cell. 2006;127:1223–1237. doi: 10.1016/j.cell.2006.10.037. [DOI] [PubMed] [Google Scholar]
- Mahadevan S., Struhl K. Tc, an unusual promoter element required for constitutive transcription of the yeast HIS3 gene. Mol Cell Biol. 1990;10:4447–4455. doi: 10.1128/MCB.10.9.4447. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Maillet L., Collart M.A. Interaction between Not1p, a component of the Ccr4-not complex, a global regulator of transcription, and Dhh1p, a putative RNA helicase. J Biol Chem. 2002;277:2835–2842. doi: 10.1074/jbc.M107979200. [DOI] [PubMed] [Google Scholar]
- Malvar T., Biron R.W., Kaback D.B., Denis C.L. The CCR4 protein from Saccharomyces cerevisiae contains a leucinerich repeat region which is required for its control of ADH2 gene expression. Genetics. 1992;132:951–962. doi: 10.1093/genetics/132.4.951. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mauxion F., Faux C., Séraphin B. The BTG2 protein is a general activator of mRNA deadenylation. EMBO J. 2008;27:1039–1048. doi: 10.1038/emboj.2008.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miyasaka T., Morita M., Ito K., Suzuki T., Fukuda H., Takeda S., Inoue J., Semba K., Yamamoto T. Interaction of antiproliferative protein Tob with the CCR4-NOT deadenylase complex. Cancer Sci. 2008;99:755–761. doi: 10.1111/j.1349-7006.2008.00746.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moqtaderi Z., Bai Y., Poon D., Weil P.A., Struhl K. TBPassociated factors are not generally required for transcriptional activation in yeast. Nature. 1996;383:188–191. doi: 10.1038/383188a0. [DOI] [PubMed] [Google Scholar]
- Morel A.P., Sentis S., Bianchin C., Le Romancer M., Jonard L., Rostan M.C., Rimokh R., Corbo L. BTG2 antiproliferative protein interacts with the human CCR4 complex existing in vivo in three cell-cycle-regulated forms. J Cell Sci. 2003;116:2929–2936. doi: 10.1242/jcs.00480. [DOI] [PubMed] [Google Scholar]
- Morita M., Suzuki T., Nakamura T., Yokoyama K., Miyasaka T., Yamamoto T. Depletion of mammalian CCR4b deadenylase triggers elevation of the p27Kip1 mRNA level and impairs cell growth. Mol Cell Biol. 2007;27:4980–4990. doi: 10.1128/MCB.02304-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakamura T., Yao R., Ogawa T., Suzuki T., Ito C., Tsunekawa N., Inoue K., Ajima R., Miyasaka T., Yoshida Y., et al. Oligoastheno-teratozoospermia in mice lacking Cnot7, a regulator of retinoid X receptor beta. Nat Genet. 2004;36:528–533. doi: 10.1038/ng1344. [DOI] [PubMed] [Google Scholar]
- Oberholzer U., Collart M.A. Characterization of NOT5 that encodes a new component of the Not protein complex. Gene. 1998;207:61–69. doi: 10.1016/S0378-1119(97)00605-7. [DOI] [PubMed] [Google Scholar]
- Prévôt D., Voeltzel T., Birot A.M., Morel A.P., Rostan M.C., Magaud J.P., Corbo L. The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation. J Biol Chem. 2000;275:147–153. doi: 10.1074/jbc.275.1.147. [DOI] [PubMed] [Google Scholar]
- Prévôt D., Morel A.P., Voeltzel T., Rostan M.C., Rimokh R., Magaud J.P., Corbo L. Relationships of the antiproliferative proteins BTG1 and BTG2 with CAF1, the human homolog of a component of the yeast CCR4 transcriptional complex: involvement in estrogen receptor alpha signaling pathway. J Biol Chem. 2001;276:9640–9648. doi: 10.1074/jbc.M008201200. [DOI] [PubMed] [Google Scholar]
- Rouault J.P., Prévôt D., Berthet C., Birot A.M., Billaud M., Magaud J.P., Corbo L. Interaction of BTG1 and p53-regulated BTG2 gene products with mCaf1, the murine homolog of a component of the yeast CCR4 transcriptional regulatory complex. J Biol Chem. 1998;273:22563–22569. doi: 10.1074/jbc.273.35.22563. [DOI] [PubMed] [Google Scholar]
- Seufert W., Jentsch S. Ubiquitin-conjugating enzymes UBC4 and UBC5 mediate selective degradation of short-lived and abnormal proteins. EMBO J. 1990;9:543–550. doi: 10.1002/j.1460-2075.1990.tb08141.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thore S., Mauxion F., Séraphin B., Suck D. X-ray structure and activity of the yeast Pop2 protein: a nuclease subunit of the mRNA deadenylase complex. EMBO Rep. 2003;4:1150–1155. doi: 10.1038/sj.embor.7400020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tucker M., Valencia-Sanchez M.A., Staples R.R., Chen J., Denis C.L., Parker R. The transcription factor associated Ccr4 and Caf1 proteins are components of the major cytoplasmic mRNA deadenylase in Saccharomyces cerevisiae. Cell. 2001;104:377–386. doi: 10.1016/S0092-8674(01)00225-2. [DOI] [PubMed] [Google Scholar]
- Tucker M., Staples R.R., Valencia-Sanchez M.A., Muhlrad D., Parker R. Ccr4p is the catalytic subunit of a Ccr4p/Pop2p/Notp mRNA deadenylase complex in Saccharomyces cerevisiae. EMBO J. 2002;21:1427–1436. doi: 10.1093/emboj/21.6.1427. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Viswanathan P., Chen J., Chiang Y.C., Denis C.L. Identification of multiple RNA features that influence CCR4 deadenylation activity. J Biol Chem. 2003;278:14949–14955. doi: 10.1074/jbc.M211794200. [DOI] [PubMed] [Google Scholar]
- Washio-Oikawa K., Nakamura T., Usui M., Yoneda M., Ezura Y., Ishikawa I., Nakashima K., Noda T., Yamamoto T., Noda M. Cnot7-null mice exhibit high bone mass phenotype and modulation of BMP actions. J Bone Miner Res. 2007;22:1217–1223. doi: 10.1359/jbmr.070411. [DOI] [PubMed] [Google Scholar]
- Whisstock J.C., Romero S., Gurung R., Nandurkar H., Ooms L.M., Bottomley S.P., Mitchell C.A. The inositol polyphosphate 5-phosphatases and the apurinic/apyrimidinic base excision repair endonucleases share a common mechanism for catalysis. J Biol Chem. 2000;275:37055–37061. doi: 10.1074/jbc.M006244200. [DOI] [PubMed] [Google Scholar]
- Yamashita A., Chang T.C., Yamashita Y., Zhu W., Zhong Z., Chen C.Y., Shyu A.B. Concerted action of poly(A) nucleases and decapping enzyme in mammalian mRNA turnover. Nat Struct Mol Biol. 2005;12:1054–1063. doi: 10.1038/nsmb1016. [DOI] [PubMed] [Google Scholar]
- Yang X., Morita M., Wang H., Suzuki T., Yang W., Luo Y., Zhao C., Yu Y., Bartlam M., Yamamoto T., et al. Crystal structures of human BTG2 and mouse TIS21 involved in suppression of CAF1 deadenylase activity. Nucleic Acids Res. 2008;36:6872–6881. doi: 10.1093/nar/gkn825. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhao J., Hyman L., Moore C. Formation of mRNA 3 ends in eukaryotes: mechanism, regulation, and interrelationships with other steps in mRNA synthesis. Microbiol Mol Biol Rev. 1999;63:405–445. doi: 10.1128/mmbr.63.2.405-445.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]