From the Laboratory of Gene Transcription, Institut de Recherches Cliniques de Montréal, Montréal, Quebec H2W 1R7, Canada
Received for publication, November 22, 2002, and in revised form, January 16, 2003
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ABSTRACT |
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Site-specific protein-DNA photo-cross-linking was
used to show that, when bound to its cognate site at various distances
upstream of the TATA element, the chimeric transcriptional activator
GAL4-VP16 can physically interact with a TATA box-binding protein
(TBP)- transcription factor IIA (TFIIA)-TFIIB complex assembled on the TATA element. This result implies DNA bending and looping of promoter DNA as a result of the physical interaction between GAL4-VP16 and an
interface of the TBP-TFIIA-TFIIB complex. This protein-protein interaction on promoter DNA minimally requires the presence of one GAL4
binding site and the formation of a quaternary complex containing TBP,
TFIIB, and TFIIA on the TATA element. Notably, the topology of the
TBP-TFIIA-TFIIB-promoter complex is not altered significantly by the
interaction with DNA-bound activators. We also show that the ability of
GAL4-VP16 to activate transcription through a single GAL4 binding site
varies according to its precise location and orientation relative to
the TATA element and that it can approach the efficiency obtained with
multiple binding sites. Taken together, our results indicate
that the spatial positioning of the DNA-bound activation domain is
important for efficient activation, possibly by maximizing its
interactions with the transcriptional machinery including the
TBP-TFIIA-TFIIB-promoter quaternary complex.
Most models of transcriptional activation imply a physical
interaction of DNA-bound transcriptional activators and the
transcription machinery assembled on core promoters (1-3). This
contact between the activation domain and components of the
transcription machinery has been attributed diverse functions
including: (i) the recruitment of key transcription factors
(e.g. general transcription factors or co-activators) at the
promoter, (ii) the stimulation of enzymatic activities involved in the
transcription reaction (e.g. promoter melting,
phosphorylation, initiation of RNA chain synthesis), and (iii) the
relief of transcriptional blockades induced by various types of
repressors including nucleosomes. In support of this view of
transcriptional activation, a number of protein-protein interactions
between various activation domains and members of the RNA polymerase II
(RNAPII)1 transcription
machinery have been characterized in solution and found to be important
in mediating transcriptional activation (1-3). However, little is
known about the formation of these protein-protein interactions when
the interacting partners are bound to promoter DNA.
Ultimately, transcriptional activators regulate the activity of the
basal RNAPII transcription machinery. The transcription reaction is a
multi-step process in which a preinitiation complex containing TBP,
TFIIB, TFIIE, TFIIF, TFIIH, and RNAPII is first assembled onto promoter
DNA (4, 5). TBP recognizes and binds the TATA element, inducing a bend
of about 80° in the DNA helix (6, 7). TFIIB binds to and stabilizes
the TBP-promoter complex (8). TFIIF, a factor composed of two subunits
called RAP74 and RAP30, binds tightly to RNAPII (9, 10), recruits the enzyme to the TBP-TFIIB-promoter complex, and induces an isomerization of the preinitiation complex that includes wrapping of promoter DNA
around RNAPII (11, 12). TFIIE, a factor also composed of two subunits
called TFIIE The acidic activator GAL4-VP16 is a chimeric polypeptide composed of
the DNA-binding domain of the yeast GAL4 protein (amino acids 1-147)
and the transcriptional acidic activation domain of the viral protein
VP16 (amino acids 412-490) (26). When GAL4 DNA-binding sites are
located upstream of the TATA box of a promoter, this activator has been
shown to stimulate transcription in a synergistic manner both in
vivo and in vitro (see Ref. 27 for example). GAL4-VP16
can act on various steps of the transcription reaction, probably via
its many interactions with components of the basal transcriptional
machinery. These include interactions with TBP (28, 29), TFIIB (30,
31), TFIIA (32), TFIIH (33), and hTAFII32 (34). GAL4-VP16
was shown to stimulate three distinct events during the formation of
the preinitiation complex: (i) formation of the TFIID-TFIIA-DNA complex
(34); (ii) TFIIB recruitment (35); and, (iii) RAP30, TFIIE Using site-specific protein-DNA photo-cross-linking, we have analyzed
the physical interaction between GAL4-VP16 molecules bound to promoter
sites various distances from the TATA element and a complex
containing TBP, TFIIB, and TFIIA assembled onto the TATA element. Using
templates with either one or five GAL4 DNA-binding sites, we show that
DNA-bound GAL4-VP16 does indeed cross-link to many positions in the
vicinity of the TATA element where a TBP-TFIIA-TFIIB complex is
assembled. Interaction with DNA-bound GAL4-VP16 does not significantly
modify the conformation of the TBP-TFIIA-TFIIB-promoter complex. We
also show that a GAL4-VP16 dimer bound to one GAL4 binding site can
stimulate transcription with an efficiency approaching that of
GAL4-VP16 dimers bound to five sites if the single dimer is properly
positioned upstream of the TATA box.
Protein Factors--
Recombinant yeast TBP (29), human TFIIB
(41), human TFIIA (42), and GAL4-VP16 (43) were purified as described
previously. The activity of all purified proteins was tested in various
DNA binding assays and in in vitro transcription reactions.
In Vitro Transcription--
In vitro transcriptions
were performed as described previously (44). Promoters containing the
adenovirus-2 major late (Ad2ML) promoter from nucleotides Primer Extension Analysis--
Primer extension analyses were
performed as previously described (45). Transcription reactions were
incubated with a radiolabeled 30-mer complementary to nucleotides +37
to +67 of the coding strand of the Ad2ML promoter. This primer was
labeled with [ Protein-DNA Photo-cross-linking--
The synthesis of the
photoreactive nucleotide N3R-dUMP, the preparation of the
probes, and the conditions for the binding reactions were performed as
previously described (46). Photoprobes containing the photoreactive
nucleotide at positions DNA-bound GAL4-VP16 Specifically Cross-links to the Region of the
TATA Box in the Presence of TBP, TFIIA, and TFIIB--
Most models of
transcriptional activation stipulate that an activator bound to its
specific binding site upstream of the basal promoter could make
contacts with the transcriptional machinery at the basal promoter
through the formation of a loop in the promoter DNA (reviewed in Refs.
1-3). To obtain direct evidence of the interaction of activators with
the transcriptional machinery on promoter DNA (as opposed to
interactions between free molecules in solution), we asked whether or
not GAL4-VP16 bound to its cognate sites upstream of the TATA box could
cross-link to the region of TATA in the presence of TBP, TFIIB, and
TFIIA. All three of these factors previously have been shown to bind to
the activation domain of VP16 in solution (28-32). To perform the
cross-linking experiments with a template that supports transcriptional
activation, we tested the ability of templates carrying between two and
five GAL4 binding sites, placed in both possible orientations upstream of the TATA box, to support GAL4-VP16 activation in vitro
from the Ad2ML promoter. As summarized in Fig.
1, the template with five GAL4 sites most
efficiently supported transcriptional activation by GAL4-VP16 in a HeLa
nuclear extract (11.9-fold). Notably, we were unable to obtain
synergistic activation of this promoter under our experimental
conditions. We then decided to use the template carrying five GAL4
sites (GML 33) in our photo-cross-linking experiments. As shown in Fig.
2A, GAL4-VP16 does cross-link
to photoprobe DNA-bound GAL4-VP16 Does Not Significantly Modify the Conformation
of a TBP-TFIIA-TFIIB Complex on Promoter DNA--
We and others have
previously shown that TBP and TFIIA cross-link to a number of positions
in the region of the TATA element of a promoter (47-49). We next
compared the cross-linking of TBP and TFIIA at positions
Our results also show that the cross-linking of TBP and TFIIA to
positions
We have been unable to obtain cross-linking of DNA-bound GAL4-VP16 in
the region of the TATA box in the presence of TBP alone, TBP and TFIIA,
or TBP and TFIIB (data not shown), indicating that a
TBP-TFIIA-TFIIB-promoter quaternary complex is minimally required to
produce DNA looping and stable binding to DNA-bound
GAL4-VP16. We did obtain cross-linking of DNA-bound GAL4-VP16 to the
TATA box when we used photoprobes carrying a single GAL4 binding site (Fig. 4). This cross-linking signal is
specific because most of it was lost in experiments performed in the
absence of TBP, TFIIA, and TFIIB or when we used a template lacking
GAL4 binding sites (data not shown). This result indicates that a
single GAL4-VP16 dimer bound to DNA can interact with a TBP-TFIIB-TFIIA
complex on the TATA box through DNA looping.
The Location and Orientation of a Single GAL4 Binding Site Relative
to the TATA Element Influences Activation Levels in Vitro--
Our
conclusion that GAL4-VP16 molecules bound to a single GAL4 binding site
can efficiently contact a TBP-TFIIA-TFIIB-promoter complex suggests
that a single GAL4 site could support efficient transcriptional
activation if it is positioned properly upstream of the core promoter.
To test the idea two series of templates with the Ad2ML basal promoter
placed under the control of one GAL4 binding site (in both possible
orientations) were constructed (Fig.
5A). In each series, the
distance between the GAL4 site and the TATA box is different, being 37 (GML 248 and 250), 39 (GML 252 and 254), 41 (GML 256 and 258), 43 (GML
260 and 262), 45 (GML 264 and 266), or 47 (GML 268 and 270) bp. Because
of the helical structure of DNA, GAL4-VP16 dimers bound to the various templates are localized on different faces of the DNA helix. Each 2-bp
increment will move the activator molecule by 72° (a full helical
turn being 360°). We used in vitro transcription assays in
either the presence or absence of GAL4-VP16 to test activation with
each of the constructs. The results are shown in Fig. 5B and
are summarized in Fig. 5C. The different
templates supported activation levels ranging from 2.3- to 7.5-fold.
This result indicates that the precise location of the GAL4 binding
site relative to the TATA element affects activation. We believe that
activation depends on the precise face of the helix where the VP16
activation domain is positioned (see Fig.
6A for a schematic
representation). As the site moves away from the TATA box, making one
full turn around the DNA helix (in 72° increments), transcription
activation increases up until the center of the site is located at
nucleotide
As shown in Fig. 5, the activation level obtained with a template
containing five GAL4 binding sites (11.7-fold) is only slightly higher
than that obtained using a template with one GAL4 site at position
Together, our results support the notion that DNA-bound GAL4-VP16 can
contact the transcription machinery around the TATA box, induce a
looping of the DNA double helix, and stimulate transcription in a
nonsynergistic manner. Although our results do not allow for the
determination of the exact cause-and-effect relationship between these events, they indicate that the positioning of DNA-bound activation domains upstream of TATA is important in activation mechanisms and fully support the concept of a crucial role for direct
physical contact between an activator and the RNAPII machinery through
promoter DNA looping. An increasing body of evidence indicates that
promoter DNA is wrapped around the transcription machinery during
transcription initiation. By making contacts with the transcription machinery, a process that induces DNA bending and looping,
transcriptional activators possibly stimulate the formation of a DNA
wrap around RNAPII.
In recent years, many reports have indicated that transcriptional
activators such as VP16 interact not only with the basal transcription
machinery but also with the Mediator (TRAP-SMCC-ARC) complex (50-52).
In yeast, the VP16 activation domain can also modify the
transcriptional status of chromatin by (i) relieving nucleosome-mediated repression through the recruitment of histone acetyltransferase complexes such as SAGA and NuA4 (53, 54) and by (ii)
targeting the Swi/Snf complex, thus facilitating chromatin remodeling (55). In mammalian cells, VP16 interacts functionally with
p300 (56, 57). The multiple interactions of a given activation domain
with various transcriptional targets are required to produce both the
high levels of activation obtained in vivo and in
vitro on chromatin templates and the synergistic response obtained
when iterative binding sites for a transcriptional activator drive the
expression of a reporter gene on nucleosome-containing templates (1-5). Although previous reports have established that VP16 binds directly to TFIIA, TBP, and TFIIB, our results indicate that, separately, these interactions are not stable when the proteins are
bound to promoter DNA and suggest that the TBP-TFIIA-TFIIB complex as a
whole entity is the target of DNA-bound GAL4-VP16 dimers. More
recently, a number of reports have shown that the ordered recruitment
(and concomitant ordered release) of many transcription factors,
including the general initiation factors, RNAPII, the Mediator complex,
and diverse chromatin-modifying complexes, is required for
gene activation in vivo (58). Here, we have provided
biochemical evidence showing that specific protein-protein interactions
between factors that are bound to distant positions on a DNA fragment
can induce the formation of a loop that is important for
transcriptional activation. The loop structure may be a key topological
requirement for the association of some transcription complexes to
promoter DNA. For example, and as we have suggested previously (22),
the loop structure formed within promoter DNA as a result of the
assembly of a TFIID-TFIIA-promoter complex (59) can provide the
architectural requirement for the subsequent binding of the RNAPII
complex. Rapid, tightly regulated association-dissociation of
transcription complexes on promoter DNA could be facilitated by the
formation of the loop structure. In support of this notion, topological
constraints imposed to promoter DNA such as tight bending in the TATA
box and initiation site regions were suggested to be involved in the
displacement of a key repressive nucleosome during activation of the
interferon-
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MATERIALS AND METHODS
RESULTS AND DISCUSSION
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and TFIIE
, stabilizes the preinitiation complex (13)
and is involved in the melting of promoter DNA at the transcription
initiation site through an ATP-independent mechanism (14, 15). TFIIH, a
nine-subunit factor that has both kinase and helicase activities,
mediates the ATP-dependent melting of promoter DNA and is
involved in the transition between the initiation and elongation states
of the complex (16-21) (also see Ref. 22 for a review). The initiation
of chain synthesis proceeds through a cycle of abortive initiation
events during which RNAPII synthesizes short 2-10-nucleotide
transcripts before escaping the promoter and entering a productive
elongation mode (23). The activity of elongating RNAPII is modulated
through the action of a number of elongation factors (24, 25).
, and
RNAPII recruitment (36). A number of reports indicate that GAL4-VP16 can also act on open complex formation (37), transcript elongation (38), and reinitiation (39, 40).
MATERIALS AND METHODS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS AND DISCUSSION
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50 to +10
fused to a G-less cassette and a varying number of GAL4 DNA-binding
sites were used. Supercoiled template DNA (300 ng) and competitor DNA
(300 ng, empty vector) were incubated with 1-5 µl of HeLa nuclear
extract in both the absence and presence of 5-40 ng of GAL4-VP16.
Transcript formation was monitored by primer extension and quantified
using a PhosphorImager (Amersham Biosciences).
-32P]ATP using T4 polynucleotide kinase
(United States Biochemical).
45/
48,
39/
40,
34,
20,
19, and
15 were used. A typical reaction contained 100 ng of TBP, 100 ng of
TFIIB, 200 ng TFIIA, and various amounts of GAL4-VP16 (as indicated in
the figures). UV irradiation, nuclease treatment, and SDS-PAGE analysis
of radiolabeled photo-cross-linking products were performed as
described previously (46).
RESULTS AND DISCUSSION
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS AND DISCUSSION
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39/
40 in the presence of TBP, TFIIB, and TFIIA
(left panel). As expected, the p55 subunit of both
recombinant TFIIA and TBP also cross-linked to photoprobe
39/
40
(Refs. 47-49; see below). The intensity of the GAL4-VP16
cross-linking signal in the presence of TBP, TFIIA, and TFIIB is about
30-fold higher than that obtained in the absence of TBP, TFIIA, and
TFIIB (right panel). To ensure that the cross-linking of
GAL4-VP16 to positions
39/
40 in the presence of TBP, TFIIA, and
TFIIB requires binding of Gal-VP16 to the GAL4 sites located 37 bp
upstream of TATA, we compared cross-linking signals obtained with
photoprobes possessing or lacking GAL4 binding sites. Fig.
2B shows that the cross-linking of GAL4-VP16 to photoprobe
39/
40 is dependent upon the presence of the GAL4 binding sites.
Together, these results indicate that a TBP-TFIIA-TFIIB-GAL4-VP16
complex can form on promoter DNA and that its formation requires the
presence of both the TATA element and the GAL4 binding sites, thereby
implying DNA bending and looping.
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Fig. 1.
Transcriptional activation using templates
with multiple GAL4 binding sites. Various numbers of tandemly
repeated GAL4 binding sites (two sites, GML 272 and GML 274; three
sites, GML 276 and GML 278; four sites, GML 280 and GML 282; five
sites, GML 33) were placed in both possible orientations 37 bp upstream
of the TATA box of the Ad2ML basal promoter fused to a G-less cassette.
Maximal activation levels, expressed as the ratio of the number of
transcripts produced in the presence GAL4-VP16 to that produced in its
absence (fold activation), represent an average of 3-5 independent
experiments.
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Fig. 2.
Photo-cross-linking of GAL4-VP16 to positions
39/-40. A, photo-cross-linking experiments with
photoprobe
39/
40 performed in the presence of increasing amounts of
GAL4-VP16 either in the presence or absence of TBP, TFIIA, and TFIIB.
The positions of TBP, TFIIA (p55), and GAL4-VP16 and the molecular
mass markers (M) are indicated. B,
photo-cross-linking experiments with photoprobe
39/
40 performed in
the presence of TBP, TFIIA, and TFIIB with increasing amounts of
GAL4-VP16 on templates carrying either five GAL4 binding sites or ones
lacking a GAL4 binding site. The positions of TBP, TFIIA (p55), and
GAL4-VP16 and the molecular mass markers (M) are
indicated.
45/
48,
34,
20,
19, and
15 in both the presence and the absence of
GAL4-VP16 (Fig. 3). GAL4-VP16 specifically cross-linked to all of the photoprobes except
19. In the
context of DNA looping, this finding is not surprising because five
GAL4-VP16 dimers bound to a stretch of 100 bp of DNA
(e.g. the five GAL4 binding sites) are expected to
make multiple contacts with the TBP-TFIIA-TFIIB complex associated with
the TATA box region.
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Fig. 3.
Photo-cross-linking of TBP, TFIIA, and
GAL4-VP16 to different positions along promoter DNA.
Photo-cross-linking experiments with photoprobes 45/
48,
34,
20,
19, and
15 were performed in the presence of TBP, TFIIB, and TFIIA
with increasing amounts of GAL4-VP16 on templates containing five GAL4
binding sites. The positions of TBP, TFIIA (p55), and GAL4-VP16 are
indicated.
39/
40 (Fig. 2),
34,
20,
19, and
15 (Fig. 3) is
not significantly affected by the presence of GAL4-VP16. However, the
cross-linking of TFIIA to photoprobe
45/
48 is weakly, but
reproducibly, increased by increasing amounts of GAL4-VP16. Because
this stimulation of the TFIIA cross-links by GAL4-VP16 is observed only
at positions
45/
48, it is unlikely to be the result of either a
general stabilization or a more efficient assembly of the
TBP-TFIIA-TFIIB-promoter complex. We favor the alternative conclusion
that DNA looping, induced by the contact of DNA-bound GAL4-VP16 with
the TBP-TFIIA-TFIIB complex on the TATA box, tethers the DNA helix at
45/
48 to the bulk of TFIIA (see Fig. 6B for a schematic representation).
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Fig. 4.
Photo-cross-linking of GAL4-VP16 on templates
containing a single GAL4 binding site. Cross-linking results using
photoprobe 39/
40 carrying either five (GML 33) or only one (GML
258) GAL4 binding site(s) are compared. Experiments were performed with
increasing amounts of GAL4-VP16 in the presence of TBP, TFIIA, and
TFIIB.
80 and then decreases thereafter. This finding argues in
favor of a preferred orientation, or side, of the helix for the
GAL4-VP16 activation domain such that the interactions with the
transcriptional machinery are maximized. In support of this conclusion,
the templates that most efficiently support activation are those that
place the GAL4-VP16 dimer on the same face of the DNA helix, whereas those that are least efficient place the GAL4-VP16 dimer on the opposite face of the helix (Fig. 6A).
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Fig. 5.
Transcriptional activation using templates
with a single GAL4 binding site. A, templates
containing the Ad2ML basal promoter under the control of one GAL4
binding site. The GAL4 binding site was placed in both possible
orientations (see arrows) at 37 (GML 248 and GML 250), 39 (GML 252 and GML 254), 41 (GML 256 and GML 258), 43 (GML 260 and GML
262), 45 (GML 264 and GML 266), and 47 (GML 268 and GML 270) bp from
the TATA element. The maximum activation level (fold activation) of
each template is indicated and is the average of five
experiments. B, example of the primer extension experiments
used to determine the activation levels. Experiments using the GML 33 template, which contains five GAL4 binding sites, are shown for
purposes of comparison. C, summary of our in
vitro transcription results.
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Fig. 6.
Models for the interaction of DNA-bound
GAL4-VP16 and the TBP-TFIIA-TFIIB-promoter (TATA) quaternary
complex. A, schematic representation of the
expected location of GAL4-VP16 dimers on templates carrying a single
GAL4 binding site. The figure shows a transversal view of the DNA with
GAL4-VP16 dimers positioned on various faces of the helix. The color
code represents the activation level obtained with each template:
green, forward orientation; red, reverse
orientation. Darker colors corresponds to stronger activation levels
and lighter colors to lower activation levels. B, one
GAL4-VP16 dimer bound to upstream promoter DNA (GML 258) can contact a
TBP-TFIIA-TFIIB complex positioned at the TATA box through looping of
the DNA helix. Although our results do not determine the interface of
the TBP-TFIIA-TFIIB complex that is contacted by DNA-bound GAL4-VP16,
one possibility is a domain of TFIIB (Val-135, Arg-137, Asn-139 and
Asn-140; depicted in red) that previously has been shown to
be essential for transcriptional activation (62). However, our results
indicate that this TFIIB domain alone is not sufficient for the
interaction of DNA-bound GAL4-VP16 with the transcriptional machinery
bound to core promoter. As shown, DNA looping increases the contact of
TFIIA with the DNA helix around positions 45/
48.
71
(7.5-fold). Templates containing two, 3, and four GAL4 binding sites
produced equivalent or lower activation levels (Fig. 1). In contrast to
the results of Lin et al. (27), we did not observe a
synergistic effect of multiple GAL4 binding sites on transcriptional
activation in vitro. Clearly, under our conditions, that is
using non-chromatin templates, the adequate positioning of a single
GAL4 binding site relative to TATA has an effect comparable with the
use of multiple binding sites.
gene (60, 61).
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ACKNOWLEDGEMENTS |
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We thank members of our laboratory for helpful discussions, Diane Bourque for artwork, Vincent Trinh for the design of the molecular models in Fig. 6, and Will Home for critical reading of the manuscript.
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FOOTNOTES |
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* This work was supported by a grant from the Canadian Institutes of Health Research.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Senior scholar from the Fonds de recherche en santé du
Québec. To whom correspondence should be addressed: Laboratory of Gene Transcription, Institut de Recherches Cliniques de Montréal, 110 Ave. des Pins Ouest, Montréal, Québec H2W 1R7, Canada.
Tel.: 514-987-5662; Fax: 514-987-5663; E-mail:
coulomb@ircm.qc.ca.
Published, JBC Papers in Press, January 21, 2003, DOI 10.1074/jbc.M211938200
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ABBREVIATIONS |
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The abbreviations used are: RNAPII, RNA polymerase II; Ad2ML, adenovirus-2 major late; RAP, RNA polymerase II-associated protein; TBP, TATA box-binding protein; TF, transcription factor.
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