Human transcription factor IIA

Details Human transcription factor IIA Human transcription factor IIA

1995-04-11

1997-07-29

Elliott, George C.

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

4353201, 435 9141, 435348, 435365, 435358, 435366, 435419, 530350, 536 235, C07H 2104, C07K 14435, C12N 1500

Patent

active

056521170

DESCRIPTION:

BRIEF SUMMARY
This invention relates to newly identified polynucleotides, polypeptides encoded by such polynucleotides, the use of such polynucleotides and polypeptides, as well as the production of such polynucleotides and polypeptides. More particularly, the polypeptide of the present invention is the small (.gamma.) subunit of human transcription factor IIA, sometimes hereinafter referred to as "small subunit". The invention also relates to inhibiting the action of such polypeptides.
In prokaryotes, simply mixing purified RNA polymerase, a template carrying a promoter, nucleoside triphosphates, and appropriate buffer and salts is sufficient to obtain specific gene transcription in vitro beginning at the correct sites. Purified RNA polymerase from eukaryotes, however, initiates transcription very poorly and essentially at random. Accordingly, accessory factors are required for accurate initiation of transcription in eukaryotes. Some of these transcription factors are general factors required for initiation at all promoters, while others are gene-specific and are required only for certain promoters. Among the general factors is a protein called Transcription Factor IID "TFIID", which binds to a TATA sequence, wherein T represents thymidine and A represents adenosine, in promoters. Other general factors are also involved in the assembly of a multicomponent protein complex at the promoter.
In general, transcription factors are found to contain two functional domains, one for DNA-binding and one for transcriptional activation. .These functions often reside within circumscribed structural domains that retain their function when removed from their natural context. The DNA-binding domains of transcription factors fall into several structural families based on their primary amino acid sequence.
In order to identify the specific nucleotides that control gene expression, regions of the gene flanking the coding region can be sequenced. Comparisons of these sequences reveal common patterns near the 5' and 3' ends of different genes. These are predicted to be important for proper transcription by RNA polymerase. The most common motif is the TATA sequence around 30 bp from the transcriptional start site. Other conserved sequences have been found roughly 50 to 100 bp upstream of the transcriptional start site.
Eukaryotic transcriptional activation requires the characterization of several multiprotein complexes, referred as general transcription factors and coactivators.sup.1.2. The heteromeric general transcription factor TFIIA binds directly to the TATA binding protein (TBP).sup.3.4 and has been implicated in the process of transcriptional activation.sup.5-8. The .gamma. subunit of TFIIA binds weakly to the TATA binding protein, but strongly stabilized the binding of the large subunit of TFIIA (.alpha. .beta.) to TBP. Recombinant human TFIIA is functional for the transcriptional activation mediated by at least three distinct activators. Both the .alpha. .beta. and .gamma. subunits are essential for activator dependent stimulation of TFIID by binding to promoter DNA, thus facilitating the first step in preinitiation complex formation. This demonstrates that TFIIA is an evolutionary conserved general transcription factor important for activator regulated transcription.
The interaction of TFIIA with the general transcription factor IID (TFIID) has been shown to be rate-limiting step in the transcriptional activation process.sup.5. TFIIA binds directly to TBP.sup.3.4, the DNA binding subunit of the multiprotein TFIID complex.sup.12. TBP associated factors (TAFs).sup.12-14, which are essential for activated transcription, are also required for an activator-dependent stimulation of the TFIIA-TFIID-promoter complex.sup.6. While TFIIA has no known function in unregulated basal transcription.sup.15, it has been postulated that TFIIA plays a role in preventing inhibitors of TFIID from repressing transcription.sup.16-19.
A TFIIA homolog has been identified in yeast.sup.9-10, and the genes encoding the two subunits are essential for viability.

REFERENCES:
Ranish et al., "Isolation of Two Genes That Encode Subunits of the Yeast Transcription Factor IIA", Science, vol. 255, pp. 1127-1129. Feb. 28, 1992.
Cortes et al., "Factors Involved in Specific Transcription by Mammalian RNA Polymerase II: Purification and Analysis of Transcription Factor IIA and Identification of Transcription Factor IIJ", Molecular and Cellular Biology, vol. 12, No. 1, p. 4 Jan. 1992.
Buratowski et al., "Five Intermediate Complexes in Transcription Initiation by RNA Polymerase II", Cell, vol. 56, No. 4, pp. 549-561. Feb. 24, 1989.
PCT International Search Report.
Buratowski, Cell, Apr. 8, 1944, vol. 77, pp. 1-3.
Buratowski, et al., Cell, pp. 549-561.
Gould, et al., Proc. Nat'l Acad. Sci., Mar. 1989, vol. 86, pp. 1934-1938.
Matsudaira, The Journal of BioChem, Jul. 25, 1987, vol. 262, No. 21, pp. 10035-10038.
Lathe, J. Molec. Biol., 1985, vol. 185, pp.1-12.
Tjian et al., Cell, Apr. 8, 1994, vol. 77, pp. 5-8.
Ranish, et al., Science, Feb. 28, 1992, vol. 255, pp. 1127-1129.

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