Skip to main content
SpringerLink
Log in

Genome wide expression analysis of the CCR4-NOT complex indicates that it consists of three modules with the NOT module controlling SAGA-responsive genes

  • Original Paper
  • Published:
Molecular Genetics and Genomics Aims and scope Submit manuscript

Abstract

Of the nine known members of the CCR4-NOT complex, CCR4/CAF1 are most important in mRNA deadenylation whereas the NOT1-5 proteins are most critical for transcriptional repression. Whole genome microarray analysis using deletions in seven of the CCR4-NOT genes was used to determine the overall mRNA expression patterns that are affected by members of the yeast CCR4-NOT complex. Under glucose conditions, ccr4 and caf1 displayed a high degree of similarity in the manner that they affected gene expression. In contrast, the not deletions were similar in the way they affected genes, but showed no correlation with that of ccr4/caf1. A number of groups of functionally related proteins were specifically controlled by the CCR4/CAF1 or NOT modules. Importantly, the NOT proteins preferentially affected SAGA-controlled gene expression. Also, both the CCR4/CAF1 and NOT group of proteins shared much greater similarities in their effects on gene expression during the stress of glucose deprivation. BTT1, a member of the nascent polypeptide association complex that binds the ribosome, was shown to be a tenth member of the CCR4-NOT complex, interacting through CAF130. Microarray analysis indicated that BTT1 and CAF130 correlate very highly in their control of gene expression and preferentially repress genes involved in ribosome biogenesis. These results indicate that distinct portions of the CCR4-NOT complex control a number of different cellular processes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Albert TK, Hanzawa H, Legtenberg YI, de Ruwe MJ, van den Heuvel FA, Collart MA, Boelens R, Timmers HT (2002) Identification of a ubiquitin-protein ligase subunit within the CCR4-NOT transcription repressor complex. Embo J 21:355–364

    Article  PubMed  CAS  Google Scholar 

  • Badarinarayana V, Chiang YC, Denis CL (2000) Functional interaction of CCR4-NOT proteins with TATAA-binding protein (TBP) and its associated factors in yeast. Genetics 155:1045–1054

    PubMed  CAS  Google Scholar 

  • Bai Y, Salvadore C, Chiang YC, Collart MA, Liu HY, Denis CL (1999) The CCR4 and CAF1 proteins of the CCR4-NOT complex are physically and functionally separated from NOT2, NOT4, and NOT5. Mol Cell Biol 19:6642–6651

    PubMed  CAS  Google Scholar 

  • Basehoar AD, Zanton SJ, Pugh BF (2004) Identification and distinct regulation of yeast TATA box-containing genes. Cell 116:699–709

    Article  PubMed  CAS  Google Scholar 

  • Bebenek K, Roberts JD, Kunkel TA (1992) The effects of dNTP pool imbalances on frameshift fidelity during DNA replication. J Biol Chem 267:3589–3596

    PubMed  CAS  Google Scholar 

  • Benson JD, Benson M, Howley PM, Struhl K (1998) Association of distinct yeast Not2 functional domains with components of Gcn5 histone acetylase and Ccr4 transcriptional regulatory complexes. Embo J 17:6714–6722

    Article  PubMed  CAS  Google Scholar 

  • Chabes A, Georgieva B, Domkin V, Zhao X, Rothstein R, Thelander L (2003) Survival of DNA damage in yeast directly depends on increased dNTP levels allowed by relaxed feedback inhibition of ribonucleotide reductase. Cell 112:391–401

    Article  PubMed  CAS  Google Scholar 

  • Chen J, Chiang YC, Denis CL (2002) CCR4, a 3′–5′ poly(A) RNA and ssDNA exonuclease, is the catalytic component of the cytoplasmic deadenylase. Embo J 21:1414–1426

    Article  PubMed  CAS  Google Scholar 

  • Chen J, Rappsilber J, Chiang YC, Russell P, Mann M, Denis CL (2001) Purification and characterization of the 1.0 MDa CCR4-NOT complex identifies two novel components of the complex. J Mol Biol 314:683–694

    Article  PubMed  CAS  Google Scholar 

  • Collart MA (1996) The NOT, SPT3, and MOT1 genes functionally interact to regulate transcription at core promoters. Mol Cell Biol 16:6668–6676

    PubMed  CAS  Google Scholar 

  • Collart MA, Struhl K (1993) CDC39, an essential nuclear protein that negatively regulates transcription and differentially affects the constitutive and inducible HIS3 promoters. Embo J 12:177–186

    PubMed  CAS  Google Scholar 

  • Collart MA, Struhl K (1994) NOT1(CDC39), NOT2(CDC36), NOT3, and NOT4 encode a global-negative regulator of transcription that differentially affects TATA-element utilization. Genes Dev 8:525–537

    Article  PubMed  CAS  Google Scholar 

  • Collart MA, Timmers HT (2004) The eukaryotic Ccr4-not complex: a regulatory platform integrating mRNA metabolism with cellular signaling pathways? Prog Nucleic Acid Res Mol Biol 77:289–322

    Article  PubMed  CAS  Google Scholar 

  • Daugeron MC, Mauxion F, Seraphin B (2001) The yeast POP2 gene encodes a nuclease involved in mRNA deadenylation. Nucleic Acids Res 29:2448–2455

    Article  PubMed  CAS  Google Scholar 

  • De Hoon MJL., Imoto S, Nolan J, Miyano S (2004) Open source clustering software, Bioinformatics 20:1453–1454

    Article  PubMed  CAS  Google Scholar 

  • Deluen C, James N, Maillet L, Molinete M, Theiler G, Lemaire M, Paquet N, Collart MA (2002) The Ccr4-not complex and yTAF1 (yTaf(II)130p/yTaf(II)145p) show physical and functional interactions. Mol Cell Biol 22:6735–6749

    Article  PubMed  CAS  Google Scholar 

  • Denis CL (1984) Identification of new genes involved in the regulation of yeast alcohol dehydrogenase II. Genetics 108:833–844

    PubMed  CAS  Google Scholar 

  • Denis CL, Chen J (2003) The CCR4-NOT complex plays diverse roles in mRNA metabolism. Prog Nucleic Acid Res Mol Biol 73:221–250

    PubMed  CAS  Google Scholar 

  • Denis CL, Chiang YC, Cui Y, Chen J (2001) Genetic evidence supports a role for the yeast CCR4-NOT complex in transcriptional elongation. Genetics 158:627–634

    PubMed  CAS  Google Scholar 

  • Denis CL, Malvar T (1990) The CCR4 gene from Saccharomyces cerevisiae is required for both nonfermentative and spt-mediated gene expression. Genetics 124:283–291

    PubMed  CAS  Google Scholar 

  • Draper MP, Salvadore C, Denis CL (1995) Identification of a mouse protein whose homolog in Saccharomyces cerevisiae is a component of the CCR4 transcriptional regulatory complex. Mol Cell Biol 15:3487–3495

    PubMed  CAS  Google Scholar 

  • Franke J, Reimann B, Hartmann E, Kohlerl M, Wiedmann B (2001) Evidence for a nuclear passage of nascent polypeptide-associated complex subunits in yeast. J Cell Sci 114:2641–2648

    PubMed  CAS  Google Scholar 

  • Gasch AP, Spellman PT, Kao CM, Carmel-Harel O, Eisen MB, Storz G, Botstein D, Brown PO (2000) Genomic expression programs in the response of yeast cells to environmental changes. Mol Biol Cell 11:4241–4257

    PubMed  CAS  Google Scholar 

  • Grigull J, Mnaimneh S, Pootoolal J, Robinson MD, Hughes TR (2004) Genome-wide analysis of mRNA stability using transcription inhibitors and microarrays reveals posttranscriptional control of ribosome biogenesis factors. Mol Cell Biol 24:5534–5547

    Article  PubMed  CAS  Google Scholar 

  • Hanway D, Chin JK, Xia G, Oshiro G, Winzeler EA, Romesberg FE (2002) Previously uncharacterized genes in the UV- and MMS-induced DNA damage response in yeast. Proc Natl Acad Sci USA 99:10605–10610

    Article  PubMed  CAS  Google Scholar 

  • Holmberg C, Fleck O, Hansen HA, Liu C, Slaaby R, Carr AM, Nielsen O (2005) Ddb1 controls genome stability and meiosis in fission yeast. Genes Dev 19:853–862

    Article  PubMed  CAS  Google Scholar 

  • Hu GZ, Ronne H (1994) Yeast BTF3 protein is encoded by duplicated genes and inhibits the expression of some genes in vivo. Nucleic Acids Res 22:2740–2743

    Article  PubMed  CAS  Google Scholar 

  • Huisinga KL, Pugh BF (2004) A genome-wide housekeeping role for TFIID and a highly regulated stress-related role for SAGA in Saccharomyces cerevisiae. Mol Cell 13:573–585

    Article  PubMed  CAS  Google Scholar 

  • Ito T, Chiba T, Ozawa R, Yoshida M, Hattori M, Sakaki Y (2001) A comprehensive two-hybrid analysis to explore the yeast protein interactome. Proc Natl Acad Sci USA 98:4569–4574

    Article  PubMed  CAS  Google Scholar 

  • Jelinsky SA, Samson LD (1999) Global response of Saccharomyces cerevisiae to an alkylating agent. Proc Natl Acad Sci USA 96:1486–1491

    Article  PubMed  CAS  Google Scholar 

  • Jorgensen P, Nishikawa JL, Breitkreutz BJ, Tyers M (2002) Systematic identification of pathways that couple cell growth and division in yeast. Science 297:395–400

    Article  PubMed  CAS  Google Scholar 

  • Jorgensen P, Rupes I, Sharom JR, Schneper L, Broach JR, Tyers M (2004) A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. Genes Dev 18:2491–2505

    Article  PubMed  CAS  Google Scholar 

  • Laribee RN, Shibata Y, Mersman DP, Collins SR, Kemmeren P, Roguev A, Weissman JS, Briggs SD, Krogan NJ, Strahl BD. (2007) CCR4/NOT complex associates with the proteasome and regulates histone methylation. Proc Natl Acad Sci USA 104:5836–5841

    Article  PubMed  CAS  Google Scholar 

  • Lemaire M, Collart MA (2000) The TATA-binding protein-associated factor yTafII19p functionally interacts with components of the global transcriptional regulator Ccr4-Not complex and physically interacts with the Not5 subunit. J Biol Chem 275:26925–26934

    Article  PubMed  CAS  Google Scholar 

  • Lenssen E, Oberholzer U, Labarre J, De Virgilio C, Collart MA (2002) Saccharomyces cerevisiae Ccr4-not complex contributes to the control of Msn2p-dependent transcription by the Ras/cAMP pathway. Mol Microbiol 43:1023–1037

    Article  PubMed  CAS  Google Scholar 

  • Liu HY, Badarinarayana V, Audino DC, Rappsilber J, Mann M, Denis CL (1998) The NOT proteins are part of the CCR4 transcriptional complex and affect gene expression both positively and negatively. Embo J 17:1096–1106

    Article  PubMed  CAS  Google Scholar 

  • Liu HY, Toyn JH, Chiang YC, Draper MP, Johnston LH, Denis CL (1997) DBF2, a cell cycle-regulated protein kinase, is physically and functionally associated with the CCR4 transcriptional regulatory complex. Embo J 16:5289–5298

    Article  PubMed  CAS  Google Scholar 

  • Maillet L, Collart MA (2002) Interaction between Not1p, a component of the Ccr4-not complex, a global regulator of transcription, and Dhh1p, a putative RNA helicase. J Biol Chem 277:2835–2842

    Article  PubMed  CAS  Google Scholar 

  • Mulder KW, Brenkman AB, Inagaki A, van den Broek NJ, Marc Timmers HT (2007a) Regulation of histone H3K4 tri-methylation and PAF complex recruitment by the Ccr4-Not complex. Nucleic Acids Res 35:2428–39

    Article  PubMed  CAS  Google Scholar 

  • Mulder KW, Inagaki A, Cameroni E, Mousson F, Winkler GS, De Virgilio C, Collart MA, Timmers HT (2007b) Modulation of Ubc4p/Ubc5p-mediated stress responses by the RING-finger-dependent ubiquitin-protein ligase Not4p in Saccharomyces cerevisiae. Genetics 176:181–192

    Article  PubMed  CAS  Google Scholar 

  • Ohn T, Chiang Y.C, Lee DJ, Yao G, Zhang C, Denis CL (2007) CAF1 plays an important role in mRNA deadenylation separate from its contact to CCR4. Nucl Acids Res 35: 3002–3015

    Article  PubMed  CAS  Google Scholar 

  • Panasenko O, Landrieux E, Feuermann M, Finka A, Paquet N, Collart MA (2006) The Yeast Ccr4-Not Complex Controls Ubiquitination of the Nascent-associated Polypeptide (NAC-EGD) Complex J. Biol Chem 281:31389–31398

    Article  CAS  Google Scholar 

  • Russell P, Benson JD, Denis CL (2002) Characterization of mutations in NOT2 indicates that it plays an important role in maintaining the integrity of the CCR4-NOT complex. J Mol Biol 322:27–39

    Article  PubMed  CAS  Google Scholar 

  • Sakai A, Chibazakura T, Shimizu Y, Hishinuma F (1992) Molecular analysis of POP2 gene, a gene required for glucose-derepression of gene expression in Saccharomyces cerevisiae. Nucleic Acids Res 20:6227–6233

    Article  PubMed  CAS  Google Scholar 

  • Saldanha AJ (2004) Java Treeview—extensible visualization of microarray data. Bioinformatics 20:3246–3248

    Article  PubMed  CAS  Google Scholar 

  • Sanders SL, Jennings J, Canutescu A, Link AJ, Weil PA (2002) Proteomics of the eukaryotic transcription machinery: Identification of proteins associated with components of yeast TFIID by multidimensional mass spectrometry. Mol Cell Biol 22:4723–4738

    Article  PubMed  CAS  Google Scholar 

  • Schild D (1995) Suppression of a new allele of the yeast RAD52 gene by overexpression of RAD51, mutations in srs2 and ccr4, or mating-type heterozygosity. Genetics 140:115–127

    PubMed  CAS  Google Scholar 

  • Toyn JH, Johnston LH (1994) The Dbf2 and Dbf20 protein kinases of budding yeast are upregulated after the metaphase to anaphase cell cycle transition. Embo J 13:1103–1113

    PubMed  CAS  Google Scholar 

  • Traven A, Hammet A, Tenis N, Denis CL, Heierhorst J (2005) Ccr4-not complex mRNA deadenylase activity contributes to DNA damage responses in Saccharomyces cerevisiae. Genetics 169:65–75

    Article  PubMed  CAS  Google Scholar 

  • Tucker M, Staples RR, Valencia-Sanchez MA, Muhlrad D, Parker R (2002) Ccr4p is the catalytic subunit of a Ccr4p/Pop2p/Notp mRNA deadenylase complex in Saccharomyce cerevisiae. Embo J 21:1427–1436

    Article  PubMed  CAS  Google Scholar 

  • Tucker M, Valencia-Sanchez MA, Staples RR, Chen J, Denis CL, Parker R (2001) The transcription factor associated Ccr4 and Caf1 proteins are components of the major cytoplasmic mRNA deadenylase in Saccharomyces cerevisiae. Cell 104:377–386

    Article  PubMed  CAS  Google Scholar 

  • Viswanathan P, Ohn T, Chiang YC, Chen J, Denis CL (2004) Mouse CAF1 can function as a processive deadenylase/3′–5′-exonuclease in vitro but in yeast the deadenylase function of CAF1 is not required for mRNA poly(A) removal. J Biol Chem 279:23988–23995

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank J. Franke for sending strains and antibodies. This research was supported by an NIH grant, GM41215 and Hatch Project H291. This is Scientific Contribution 2307 from the New Hampshire Agriculture Experiment Station.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Rudman Hall, University of New Hampshire, Durham, New Hampshire, 03824, USA

    Yajun Cui, Deepti B. Ramnarain, Yueh-Chin Chiang, Jeffrey S. McMahon & Clyde L. Denis

  2. Simmons Comprehensive Cancer Center Genomics Core Facility, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Liang-Hao Ding

  3. Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Liang-Hao Ding

Authors
  1. Yajun Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Deepti B. Ramnarain
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yueh-Chin Chiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liang-Hao Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey S. McMahon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Clyde L. Denis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Clyde L. Denis.

Additional information

Communicated by S. Hohmann.

Yajun Cui, Deepti B. Ramnarain contributed equally to this manuscript.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary data (ZIP 3189 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cui, Y., Ramnarain, D.B., Chiang, YC. et al. 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 279, 323–337 (2008). https://doi.org/10.1007/s00438-007-0314-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00438-007-0314-1

Keywords

Search

Navigation