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Mol Cell Biol, March 1998, p. 1296-1302, Vol. 18, No. 3
Department of Biochemistry and Molecular
Genetics, Health Sciences Center, University of Virginia,
Charlottesville, Virginia 229081;
Cold
Spring Harbor Laboratory, Cold Spring Harbor, New York
117242; and
The Wistar Institute,
Philadelphia, Pennsylvania 191043
Received 9 September 1997/Returned for modification 17 November
1997/Accepted 9 December 1997
A large body of evidence from viral systems has established that
transcription factors play an important and direct role in activating
viral DNA replication. Among the transcriptional activation domains
that can stimulate viral DNA replication are acidic domains such as
those derived from herpes simplex virus VP16 and the tumor suppressor
p53. Here we show that acidic activation domains can also activate a
cellular origin of replication in a chromosomal context. When tethered
to the yeast ARS1 (autonomously replicating sequence 1) origin of
replication, both VP16 and p53 activation domains can enhance origin
function. In addition, the C-terminal acidic region of the yeast
transcription factor ABF1, which normally activates the ARS1 origin, is
sufficient for activating ARS1 function when tethered to the origin.
Mutations at residues Trp-53 and Phe-54 of a 20-residue (41 to 60)
activation region of p53 abolish the activation of both replication and
transcription, suggesting that the same structural determinants may be
employed to activate both processes in yeast. Furthermore, using a
two-dimensional gel electrophoresis method, we demonstrate that the
GAL4-p53 chimeric activator can activate initiation of chromosomal
replication from an origin inserted at the native ARS1 locus. These
findings strongly suggest functional conservation of the mechanisms
used by the acidic activation domains to activate viral DNA replication
in mammalian cells and chromosomal replication in yeast.
The eukaryotic origins of DNA
replication characterized to date contain two functional elements: a
core sequence that determines the site of initiation and a nearby
auxiliary element that stimulates initiation efficiency (11, 16,
36, 55). Analogous to the TATA box of a transcription promoter,
the core sequence of an origin of replication serves as the binding
site for an initiator protein which in turn nucleates the assembly of a
large initiation protein complex. The auxiliary elements of an origin
usually contain binding sites for proteins that in other DNA contexts
function as transcription factors. It has been well established that
transcription factors play an important and direct role in viral DNA
replication (15, 30, 64).
Most of our current understanding of transcription factors' role in
replication comes from studies of DNA tumor viruses (17, 33, 52,
63, 68). For example, the flanking auxiliary sequences of the
simian virus 40 and polyomavirus origins are located adjacent to the
core region that forms the binding site for the large T antigen, the
viral initiator protein. The auxiliary sequences contain binding sites
for several cellular transcription factors such as Sp1, AP1 and p53 for
simian virus 40 and AP1 and PEA3 for polyomavirus. These cis
elements act synergistically to increase the initiation frequency up to
1,000-fold (17, 25, 26). Heterologous transcription factors
can also activate viral replication when tethered to the origins of
replication. For example, factors such as NF- Transcription factors have also been implicated in activation of
cellular DNA replication. In the case of Saccharomyces
cerevisiae, a detailed mutational analysis of one origin, ARS1
(autonomously replicating sequence 1), has led to identification of two
essential elements, A and B (10, 44). Element A contains an
11-bp consensus sequence that is conserved among all origins in
S. cerevisiae. It is the binding site for the initiator
protein called origin recognition complex (ORC) (2). The B
element is composed of three functional sequences, B1, B2, and B3,
which are collectively essential for origin function (44)
and are conserved in another origin, ARS307 (50, 59). The B1
element is important for ORC binding and additional functions in
replication initiation (51, 54). The function of the B2
element is unclear. B3 is the binding site for the ABF1 protein, which,
in other contexts functions as a transcriptional activator or repressor
protein (6, 8, 18, 19, 46). ABF1 binding sites have been
found in several other ARSs; for example, the two ABF1 binding sites at
ARS121 can function as far as 1 kb from the A element (19,
65). Like enhancers in viral replication, the function of the B3
element of ARS1 in plasmid replication can be replaced by binding sites for other yeast transcription factors, such as GAL4 and RAP1
(44). However, since a large number of the sequences that
function as ARSs in plasmids do not serve as replicators in their
native chromosomal contexts (46), it is not known whether
heterologous transcription factors can substitute for the ABF1 function
in initiation of replication from the chromosomal ARS1 locus.
Acidic domains are the most extensively studied type of activation
domain in eukaryotic transcription factors (60). These activation regions, including those from yeast GAL4 and GCN4, mammalian
p53, and herpes simplex virus VP16, contain a significant number of
negatively charged residues. One salient feature of acidic activation
domains is their ability to activate transcription in cells from a
variety of eukaryotic species, including yeasts, plants, and mammals
(48). This finding indicates that the mechanisms employed by
acidic activators to stimulate transcription are highly conserved in
the eukaryotic kingdom. By analogy to transcriptional activation,
several acidic activation domains, such as those from VP16 and p53,
activate viral replication when tethered to the viral origins of DNA
replication (13, 29, 39). However, it is unclear whether the
acidic activators that activate viral DNA replication can facilitate
chromosomal DNA replication as well.
In this report, we analyze the abilities of several acidic activation
domains to stimulate DNA replication in S. cerevisiae. We
show that acidic activation domains, when tethered to the origin of
replication, can enhance replication efficiency of the ARS1 origin in
the native chromosomal locus as well in a circular plasmid. The data
also define the C-terminal acidic region of the yeast transcription
factor ABF1 as a domain important for activating normal ARS1 function.
These results strongly suggest a functional conservation of the
mechanism used by acidic activators to activate DNA replication in both
yeast and higher eukaryotes.
Strains and plasmids.
The yeast strain used in this study,
BP1
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Activation of Chromosomal DNA Replication in
Saccharomyces cerevisiae by Acidic Transcriptional
Activation Domains
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
B, VP16, E1A, bovine
polyomavirus E2, and GAL4 can stimulate polyomavirus DNA replication
(1, 24, 66). The functional promiscuity of these proteins in
activation of replication is reminiscent of the similar behavior of
these activators in transcriptional activation.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
H, is derived from BP1 (gal4::HIS4 ura3-52
leu2-2,112 his4-519 ade1) (3). The modified strain
contains a replacement of the HIS4 far-upstream sequence
between nucleotides 68624 and 68985 of chromosome III (coordinates from
the Stanford SC database) with the sequence GGAT.
View larger version (103K):
[in a new window]
FIG. 1.
GAL4-derived transcription factors can activate ARS
function in a site-dependent manner. ARS1 plasmids that carry either a
wild-type (wt) (top and middle panels) or a mutant (mut) (bottom panel)
GAL4 site were assayed for plasmid stability. The GAL4 DBD, either
alone (top panel) or fused to a duplicate sequence from the activation
domain of VP16 (middle and bottom panels), was expressed in the yeast
cells. After nonselective growth for 30 h at 30°C, the cells
were plated on medium with (left) or without (right) uracil. The ratio
of the colony numbers on the two plates is indicative of the stability
of the test plasmid. For induction of the GAL4 derivatives, a final
concentration of 10 µM copper sulfate was used.
-galactosidase reporter construct contained
two GAL4 binding sites (with the same sequence as shown above) in front
of the HIS4 TATA sequence and the lacZ gene. The
UAS of the HIS4 promoter (sequence between 68616 and 68453 of chromosome III) was deleted. The plasmid was integrated at the 3'
untranslated region of the LYS2 gene, between nucleotides
468962 and 468943 of chromosome II (coordinates from the Stanford SC
database). pGAL4-2xVN8 contained DNA sequence that encoded two repeats
of an eight-residue sequence from the VP16 activation domain
(DFDLDMLG). The double-mutant derivatives of the GAL4-p53 fusion
proteins contain either an L22Q/W23S or a W53Q/F54S mutation (9,
42).
Plasmid stability assay. The assay was performed as described previously (44). The expression vectors and the ARS1 test plasmids were transformed separately into yeast cells by the standard lithium acetate method (34). After 30 h of growth in nonselective liquid medium, the cultures were diluted and equal numbers of cells were plated on selective (synthetic complete medium [SCM]-Leu-Ura) and nonselective (SCM-Leu) plates. Unless otherwise stated, all liquid media used contained 50 µM copper sulfate for induction of the GAL4-derived fusion proteins. The stability value for each GAL4 derivative is an average of data from at least three independent experiments, each using colonies from a separate transformation.
-Galactosidase assay.
The transcription assay was
performed and the specific activity was calculated according to a
standard protocol (34). Each GAL4 derivative was tested in
at least three independent experiments.
Immunoblotting. Total cell lysates were prepared by the bead-beating method (34). The lysates were normalized for the total protein amounts and resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. After being transferred to a nitrocellulose membrane, the samples were probed with a monoclonal antibody against the hemagglutinin (HA) epitope (12CA5; Amersham). The immunoblots were developed with an ECL kit from Amersham.
2-D gel electrophoresis. Genomic DNA was prepared and replication intermediates were analyzed exactly as described previously (41). Yeast cultures were grown in SCM-Leu with 100 µM copper sulfate, except for the nonselective medium used for the positive control shown in Fig. 4B. Cultures were harvested at an optical density at 600 nm of 1.0 to 1.2. A total of 500 ml of culture was used for each two-dimensional (2-D) sample.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Plasmid stability assay for studying activation of replication by transcriptional activation domains. ARS1 in S. cerevisiae represents one of the best-characterized cellular origins in eukaryotes. The B3 element at ARS1 is the binding site for the yeast transcription factor ABF1 and can be functionally replaced by the GAL4 binding site (44). Characterization of ARS1 function largely has been done by using a plasmid stability assay (44). In this assay, yeast cells are transformed with a test plasmid containing the ARS of interest. Transformants are first grown in selective medium selecting for a marker on the plasmid, diluted into nonselective medium where the plasmid can be lost, and subsequently grown for approximately 14 generations. The percentage of yeast cells that retain the plasmid is then determined. With this assay, the wild-type ARS1 plasmid is retained in approximately 50% of yeast cells, whereas a crippled ARS1 plasmid with two mutant B elements is present in no more than 1 to 2% of yeast cells (44).
To assess the abilities of various transcriptional activation domains to stimulate ARS function, a GAL4 binding site was inserted next to a mutated B3 element. The B2 element of the same ARS1 sequence was also substituted with an 8-bp linker. Since this modified ARS1 sequence had both B2 and B3 elements inactivated, an ARS/CEN plasmid bearing the ARS1 sequence (pARS1/-B23/G24) displayed a very low stability in the absence of a GAL4-derived activator (0.6% ± 0.49%; Fig. 2C). In a separate set of constructs, transcriptional activation domains were fused to the GAL4 DBD. The N termini of the fusion proteins were also tagged with the HA epitope to facilitate their detection in yeast. The fusion gene was under the control of a copper-inducible promoter, and the construct used in this study was integrated into a chromosomal locus. Use of the inducible expression vectors alleviated the toxicity otherwise caused by high constitutive expression of some GAL4-derived activators (3). The integrated constructs also prevented possible functional interference in vivo between an expression plasmid and the test plasmid in the same yeast cells.
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A 20-residue peptide from the p53 activation domain can strongly
activate replication and transcription.
The transcriptional
activation domain of p53 has been mapped to the N-terminal 40 residues
of the protein (62). However, sequences immediately
following the region also contribute to p53 transcriptional activity
(12). In fact, a recent study has identified a new
activation domain between amino acids (aa) 40 and 83 (9).
GAL4 fusions with either subdomain (aa 1 to 40 or 40 to 83) can
activate transcription in both mammalian and yeast cells. We and others
have shown previously that the N-terminal 73 residues of p53 activate
viral DNA replication when fused to the GAL4 DBD (29, 39).
To test whether the two subdomains of p53 can independently activate
ARS function in yeast, the regions between residues 1 and 40 and
residues 41 and 60 were fused separately to the GAL4 DBD (Fig.
3A), and the chimeric proteins were
tested in both the plasmid stability assay and the -galactosidase
assay for the ability to enhance ARS1 plasmid stability and gene
expression, respectively.
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-galactosidase reporter gene
(1,868 ± 305 U versus 12.4 ± 10.5 U by the GAL4 DBD alone;
lower panel of Fig. 2C). It has been shown previously that mutations at
residues Trp-53 and Phe-54 of p53 abolish the transcriptional activity
of the second subdomain (9). When the same mutations were
introduced into the GAL4-p53(41-60) fusion protein, they abrogated
activation of both plasmid stability and transcription in yeast (3.3% ± 0.98% and 12.4 ± 5.7 U, respectively; Fig. 2C). Although we
could not exclude the possibility that the double mutations changed the
global structure of the 20-aa region of p53, the data were consistent
with the notion that the same amino acid residues were used to activate
both DNA replication and transcription. Taken together, these results
strongly suggest that the p53 region between residues 41 and 60 contains a potent activation domain for yeast transcription and ARS
function.
Given the potency of the first p53 subdomain in activating mammalian
and yeast transcription (9, 62), it was of interest to
determine whether it had a similar stimulatory effect on ARS function.
Despite repeated efforts, we were unable to detect the GAL4-p53(1-40)
protein from the yeast lysate in an immunoblotting assay (Fig. 2B, lane
4). However, expression of this protein did yield a significant
increase in -galactosidase activity in the transcription assay
compared to the GAL4 DBD alone (456 ± 241 U versus 12 ± 10 U), whereas little stimulation could be observed in the plasmid
stability assay (3.5% ± 1.5%; Fig. 2C). This result suggested that a
low level of expression of the activator was sufficient for
transcriptional activation but not for replication. Since the lack of
activation of ARS function might be due to the relatively low
sensitivity of the plasmid stability assay, it was not possible to
determine whether the first subdomain of p53 had an inherent ability to
activate replication. Mutations at residues 22 and 23 previously have
been shown to abrogate the transcriptional activity of p53
(42). Strikingly, GAL4-p53(1-40) with mutations at these two
positions was present in abundance in the yeast lysate (Fig. 2B, lane
5), which was a further indication that the wild-type GAL4-p53(1-40)
might be growth inhibitory. However, the mutant protein did not
stimulate either replication or transcription (2.1% ± 0.7% or
6.7 ± 1.9 U, respectively; Fig. 2C).
While the low protein level of GAL4-p53(1-40) in yeast complicated the
study of its potential in activating ARS function, it is of interest
that an almost identical fusion protein has been shown to undergo rapid
degradation in mammalian cells (28). In the latter case, the
oncoprotein Mdm2 binds the first 42 residues of p53 and promotes p53
degradation. Furthermore, mutations at residues 22 and 23 that disrupt
Mdm2 binding also prevent Mdm2-dependent degradation (28,
37). The same mutations also dramatically increase the protein
levels of the GAL4-p53(1-40) fusion protein in yeast, which raises an
interesting possibility that this region of p53 can bind a yeast
protein with a function similar to that of the Mdm2 protein in
mammalian cells. Alternatively, strong heterologous activation domains
that are toxic to yeast cell growth may be preferentially targeted by
the protein degradation machinery.
The C-terminal region of ABF1 is important for activation of ARS
function.
Having characterized heterologous activation domains of
DNA replication, we next determined what type of protein domain
normally activated initiation of replication at the ARS1 origin. Yeast ABF1 is a multifunctional protein that has been implicated in replication, transcriptional activation, and mating-type silencing (8). The full-length 731-residue protein can be divided into two regions (Fig. 3A): the first 530 residues are sufficient for specific DNA binding (27), and the remainder of the ABF1
protein is essential for cell viability (53). Although the
function of the highly negatively charged C-terminal region is not well understood, it has been proposed to act as an acidic activation domain
in stimulating both replication and transcription (22). To
test this hypothesis, we fused the GAL4 DBD to the C-terminal 123 aa of
ABF1. As shown in Fig. 3C, this chimeric protein (608-731) clearly
enhanced the stability of the GAL4-responsive ARS1 test plasmid,
indicating that the C-terminal portion of ABF1 was sufficient for
stimulating ARS function when tethered to the origin. However, when
tested in the transcriptional activation assay, the same fusion protein
yielded only 55 ± 17 U of -galactosidase activity, in
comparison with 1,868 ± 305 U for GAL-p53(41-60) and 12 ± 10 U for the GAL4 DBD alone. Thus, despite the fact that the C-terminal domain of ABF1 has a much higher net negative charge than the p53
activation domain (residues 41 to 60), it is a much weaker transcriptional activator under the conditions used in these
experiments.
A GAL4-derived activator can stimulate initiation of DNA replication at the ARS1 chromosomal locus. The plasmid stability assay has been valuable in dissecting the multiple genetic elements of the ARS1 sequence. All four cis elements that are involved in plasmid replication have been shown to contribute to initiation of DNA replication in their normal locations in the chromosome (44, 45). Plasmid stability, however, is affected both by the efficiency of its replication and by the efficiency of its segregation or nuclear retention. Thus, results from plasmid stability assays may not always reflect the contributions of cis-acting DNA sequences to the efficiency of initiation of DNA replication in the chromosome (46). When the ARS1 test plasmid was isolated from yeast cells at the completion of the plasmid stability assay and analyzed by DNA hybridization, there was a net increase in the total amount of plasmid DNA from the yeast population that expressed a GAL4-derived activator (data not shown). This finding supports the notion that replication efficiency of the test plasmid was indeed stimulated by the acidic activators.
To test whether GAL4-derived activators activate ARS1 replication in a chromosomal context, we used a 2-D gel electrophoresis technique to detect replication intermediates initiated from various derivatives of the chromosomal ARS1 (4). In this assay, chromosomal DNA from asynchronously growing cells was isolated and digested with a restriction endonuclease, and then the DNA fragments were separated by mass in the first dimension and subsequently by both mass and shape in the second dimension. Replication intermediates were separated from linear DNA fragments, forming arcs in the gel. Southern blotting analysis was then used to distinguish the following two types of replication intermediates: those origin-containing fragments with a characteristic bubble arc, and those that did not contain an origin but did contain a replication fork and migrated as a Y arc (Fig. 4A). A previous study has shown that simultaneous disruption of the three B elements at the ARS1 locus obliterates the bubble arc in the 2-D gel analysis, whereas removing only one or two functional B elements weakens but does not abolish the bubble arc (45). Since it is technically difficult to quantitate small differences in efficiency of origin firing by the 2-D gel method, we reasoned that a low baseline of replication in the absence of all three B elements might facilitate detection of any stimulatory effects by the GAL4-derived activators. Therefore, the three B elements at the ARS1 locus in chromosome IV were replaced with a single GAL4 binding site by homologous recombination.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Activation of DNA replication and transcription by acidic activation domains have many common characteristics. First, acidic activation domains are well known for their ability to activate transcription in a variety of eukaryotes (48). We and others have shown that the same group of activation domains can also activate chromosomal DNA replication in yeast as well as viral DNA replication in mammalian cells (this study and references 13, 29, and 39). Second, a small and well-defined peptide of VP16 and p53 activation domains is sufficient for stimulating both transcription and DNA replication. Third, the potency of an acidic activation domain in transcriptional activation in general correlates with that in activation of DNA replication (e.g., VP16 and p53 are stronger than ABF1). Finally, mutations in the acidic domains that abolish transcriptional activation also destroy their function in DNA replication. For instance, the GAL4-p53(41-60) fusion protein with mutations at residues Trp-53 and Phe-54 fails to activate yeast replication and transcription in our assays. In addition, it has been shown that mutations at the aromatic residue Phe-442 of the VP16 activation domain abrogate GAL4-VP16's ability to activate transcription and polyomavirus DNA replication (14, 29). Taken together, these studies strongly suggest that some enhancers of replication and transcription may functionally overlap. Furthermore, there may be a conserved mechanism that the acidic activation domains utilize to activate DNA replication in yeast and higher eukaryotes.
Wiltshire et al. recently reported that a 50-aa C-terminal region of
the ABF1 protein (aa 635 to 684) was sufficient to stimulate ARS121
function when tethered to the origin (67). This region partially overlaps one of the two regions that are shown in
this study to activate ARS1 function. Unlike ARS1, activation of ARS121 by ABF1 cannot be replaced by other transcription factors
(67), suggesting a special function of ABF1 at
ARS121. Compared to the VP16 and p53 activation domains, the C-terminal
region of ABF1 contains a relatively weak transcriptional activation
domain. This finding is consistent with the previous observation
that ABF1 activates transcription synergistically with other weak
activators (5). Furthermore, a LexA-ABF1 fusion protein
stimulates transcription only from a LexA-responsive promoter that
contains other cis-regulatory elements (21).
Therefore, transcriptional activation by ABF1 may require cooperation
from other transcriptional activators that bind to the same promoter
region. It is noteworthy that the 123-aa C-terminal region of ABF1 has
a much higher net negative charge (
25) than the 20-aa region from the
p53 activation domain (7), yet the latter is a much stronger
activator for both transcription and replication. It thus appears that
the number of acidic residues in an activation domain may not be the
primary determinant for the potency of activation of replication, just
as previously shown for transcriptional activation (14, 42,
61). Rather, hydrophobic residues in the acidic activation
domains may play a more critical role in activation of replication and
transcription.
Intense work in the past few years has led to a better understanding of the mechanism(s) used by acidic activators to activate transcription. Acidic domains such as those of VP16 and p53 have been shown to contact several general factors in the transcriptional machinery in vitro, suggesting multiple pathways utilized by these domains to activate transcription (49). More recent studies have also demonstrated that acidic activators can counteract the nucleosomal repression of transcription and that the antirepression function may be mediated by several chromatin remodeling systems (23, 35, 47, 56). Compared with the studies of transcriptional activation, much less is known concerning the molecular basis for activation of DNA replication by acidic activators. The activation domains of VP16 and p53 interact with replication protein A (RPA), an essential component of the replication machinery (29, 39). Furthermore, mutations that disrupt the interaction between the acidic activation domains and RPA also abolish activation of DNA replication (29). In particular, Trp-53 and Phe-54 of p53, shown in this study to be critical for activation of replication, are important for p53 binding to RPA as well (38), suggesting recruitment of RPA to the origin as one potential mechanism for activation of replication by the acidic domains. However, other mechanisms for enhancing initiation of DNA replication are also possible. For example, in vitro biochemical studies have shown that the activation domains of VP16 and p53 can antagonize the nucleosomal repression of viral DNA replication (13, 40), thus raising the possibility that these transcription factors use similar strategies to overcome the nucleosomal repression in replication and transcription. Because the plasmid stability assay can offer powerful genetic screening possibilities in yeast, it should be feasible to examine more closely the proteins that interact with the activation domains to enhance DNA replication.
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ACKNOWLEDGMENTS |
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We thank Leonard Guarente for the BP1 strain, Arnold Levine for the p53 mutant at residues 22 and 23, Yanfen Hu for help with plasmid construction, and Chun Liang for help with the 2-D gel analysis. R.L. is also grateful to Joyce Hamlin for helpful discussion and encouragement during the course of the work.
This work was supported in part by a Special Fellow Award from Leukemia Society of America, an ACS institutional research grant, and a start-up research fund from the University of Virginia (R.L.) and by funds from NIH grant RO1GM45436 to B.S.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Biochemistry, Health Sciences Center, University of Virginia, Charlottesville, VA 22908. Phone: (804) 243-2727. Fax: (804) 924-5069. E-mail: rl2t{at}virginia.edu.
Present address: Molecular Medicine Research Center, The Institute
of Medical Science, Tokai University, Bohseida, Isehara, Kanagawa
259-11, Japan.
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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