A mediator required for activation of RNA polymerase II transcription in vitro
Abstract
Activator proteins bind to enhancer DNA elements and stimulate the initiation of transcription. It has been proposed that activators contact general initiation factors at a promoter, and evidence for such direct interaction has been obtained. Studies of transcription in vitro, however, have suggested that activators might function through an intermediary molecule(s) distinct from the general factors. In the first of these studies, we exploited the finding that one activator could inhibit transcription stimulated by a second activator (activator interference or 'squelching'). This inhibition, which is attributed to competition between the activators for a common target factor, could not be relieved by addition of a large excess of general initiation factors, suggesting that the target for which activators compete is distinct from these factors. Similar conclusions came from the observation that TFIID's expressed from cloned genes fail to replace partially purified 'natural' TFIID fractions in supporting activation, evidently because they lacked some component present in the impure fractions. While these lines of evidence for a novel 'mediator' of activation were negative, we also showed that a partially purified fraction from yeast would reverse activator interference. This positive effect of a presumptive mediator provided an assay for its activity, but its role in activation was still only inferred. We now present direct evidence for a mediator which is required for stimulation of transcription in vitro by the activators GAL4-VP16 and GCN4, but which has no effect on transcription in the absence of activator protein.
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At active enhancers, BRD4 co-localises with the Mediator complex, which assembles the pre-initiation complex and RNAP to initiate transcription.
“At active enhancers, the BRD4 protein co-localises with the Mediator complex, which in turn assembles the pre-initiation complex (PIC) and RNAP to initiate transcription [66–68].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [67]
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“Direct evidence for a Mediator complex distinct from the known general factors was obtained upon further enrichment of the activity and analysis in a purified transcription system (Flanagan et al. 1991).”
BackgroundEffects of activation-defective TBP mutations on transcription initiation in yeast
Kim, T. K., Hashimoto, S., Kelleher, R. J. I., Flanagan, P., Kornberg, R., Horikoshi, M., & Roeder, R. (1994) · Nature · doi:10.1038/369252a0 · Cited by 114 · see citing works
Self-citationBonawitz, N. D., Soltau, W., Blatchley, M. R., Powers, B. L., Hurlock, A. K., Seals, L. A., Weng, J.-K., Stout, J., & Chapple, C. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.312298 · Cited by 111 · see citing works
“The genetic regulation of many eukaryotic genes requires a large co-regulatory complex known as Mediator, which physically bridges the interaction between gene-specific transcription factors and the basal transcription machinery at the core promoter (19, 20).”
BackgroundMediator Structural Conservation and Implications for the Regulation Mechanism
Cai, G., Imasaki, T., Takagi, Y., & Asturias, F. J. (2009) · Structure · doi:10.1016/j.str.2009.01.016 · Cited by 101 · see citing works
“Conserved structure and conformational changes in Mediator Following the discovery of Mediator in yeast (Flanagan et al., 1991; Kelleher et al., 1990), it was suggested that similar complexes might not be present or be as important in higher eukaryotic cells where the mechanism of transcription…”
BackgroundMediator Head module structure and functional interactions
Cai, G., Imasaki, T., Yamada, K., Cardelli, F., Takagi, Y., & Asturias, F. (2010) · Nature Structural &Molecular Biology · doi:10.1038/nsmb.1757 · Cited by 108 · see citing works
“Both basal and activated transcription are critically dependent on the Mediator comple”
BackgroundHaviv, I., Vaizel, D., & Shaul, Y. (1996) · EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00707.x · Cited by 108
Blair, W., Bogerd, H., Madore, S., & Cullen, B. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.11.7226-7234.1994 · Cited by 108 · see citing works
“To test whether the more N-terminal AAM in the highly active GAL4(1-147)-(AAM)2 fusion protein is indeed functionally important or merely provides a favorable structural context for the second, C-terminal AAM, we constructed a plasmid, termed pGAL4(1-147)-(AAAM)-(AAM), in which an active, C-terminal AAM is separated f…”
BackgroundMethodInfluentialTiley, L., Madore, S., Malim, M., & Cullen, B. (1992) · Genes & Development · doi:10.1101/gad.6.11.2077 · Cited by 106 · see citing works
Mediators of activation of fushi tarazu gene transcription by BmFTZ-F1
Li, F.-Q., Ueda, H., & Hirose, S. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.5.3013-3021.1994 · Cited by 101
“The second group consists of adaptors or mediators that are required for induced but not basal levels of transcription in a reconstituted yeast transcription system (2, 5).”
BackgroundThe multitalented Mediator complex
Carlsten, J. O. P., Zhu, X., & Gustafsson, C. M. (2013) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2013.08.007 · Cited by 92 · see citing works
Canet, J. V., Dobón, A., & Tornero, P. (2012) · The Plant Cell · doi:10.1105/tpc.112.103028 · Cited by 122 · see citing works
TFIID and human mediator coactivator complexes assemble cooperatively on promoter DNA.Preprint
Johnson, K. M., Wang, J., Smallwood, A., Arayata, C., & Carey, M. F. (2002) · Genes & Development · doi:10.1101/gad.995702 · Cited by 99 · see citing works
Structure and replication of hepatitis delta virus RNA.
Taylor, J. (2006) · Current Topics in Microbiology and Immunology · doi:10.1007/3-540-29802-9_1 · Cited by 99
Samanta, S., & Thakur, J. K. (2015) · Frontiers in Plant Science · doi:10.3389/fpls.2015.00757 · Cited by 107 · see citing works
“Mediator complex was first discovered in yeast in 1990, and within few years also reported in human (Kelleher et al., 1990; Flanagan et al., 1991; Thompson et al., 1993; Kim et al., 1994; Fondell et al., 1996; Ito et al., 1999).”
BackgroundDiverse roles of the Mediator complex in plants
Kidd, B. N., Cahill, D. M., Manners, J. M., Schenk, P. M., & Kazan, K. (2011) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2011.07.012 · Cited by 90 · see citing works
Chromatin remodeling complexes: ATP-dependent machines in action.
Johnson, C. N., Adkins, N. L., & Georgel, P. (2005) · Biochemistry and cell biology = Biochimie et biologie cellulaire · doi:10.1139/o05-115 · Cited by 98 · see citing works
“Furthermore, a number of SWI/SNF subunits, including Swi3, Swi5, and SWI2/SNF2 ATPase, have been identified as being stably associated subunits of the RNAPolymerase-II-mediator complex, an interface between specific regulatory proteins and the general transcription machinery of eukaryotes (Flanagan et al. 1991; Kim et…”
Background
- Authors
- Flanagan, P. M., Kelleher, R. J., Sayre, M. H., Tschochner, H., & Kornberg, R. D.
- Affiliations
- Stanford Medicine (US)
- Venue
- Nature
- Published
- 1991-04
- Volume
- 350
- Issue
- 6317
- Pages
- 436-438
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2062439115
- Cited by
- 386
- References
- 0
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 9 · 2023: 3 · 2022: 10 · 2021: 13 · 2020: 21 · 2019: 11 · 2018: 9 · 2017: 11 · 2016: 11 · 2015: 8 · 2014: 5 · 2013: 15 · 2012: 9
- FWCI
- 11.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- RNA polymerase II transcription, transcriptional activator, Mediator complex, TFIID, GAL4-VP16, GCN4, enhancers, transcriptional activation, yeast
- MeSH terms
- DNA-Binding Proteins, Enzyme Activation, Fungal Proteins, Nuclear Proteins, Recombinant Proteins, RNA Polymerase II, Saccharomyces cerevisiae, Transcription Factors, Transcription, Genetic, Saccharomyces cerevisiae Proteins, Transcription Factor TFIID, In Vitro Techniques
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