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From the Section of Molecular and Cellular Biology, Division of
Biological Sciences, University of California,
Davis, California 95616
INTRODUCTION RNA polymerase
(RNAP)1 II is responsible for the synthesis
of pre-mRNA in eukaryotic cells. The subunit structure of RNAP II
is similar to that of other RNAPs in that it is comprised of two large
subunits with a molecular weight in excess of 100,000 and a collection
of smaller subunits (1, 2). However, the largest subunit of RNAP II is
unique in that it contains an unusual domain at its C terminus
comprised of tandem repeats of the consensus sequence
Tyr-Ser-Pro-Thr-Ser-Pro-Ser (3). The consensus repeat has been
conserved in evolution although the number of repeats present varies in
different species. RNA polymerase II of mammalian cells contains 52 copies of the consensus repeat, and yeast contains 26-27 copies,
whereas other eukaryotes contain an intermediate number of repeats.
Although this C-terminal domain (CTD) plays an essential role in
transcription catalyzed by RNAP II, it is absent from RNAPs I and III.
The CTD of yeast and mammalian RNAP II was first reported about 10 years ago and is shown in Fig. 1 (4, 5). This domain has
provided a focal point for the analysis of RNAP II structure-function
relationships. Although our understanding of the CTD has increased
considerably in the ensuing 10 years, its precise role in transcription
remains to be established.
Temporal Relationship between Phosphorylation of CTD and
Progression of RNAP II Through Transcription Cycle Apart from the extensive repetition of the consensus repeat, the
CTD is unusual in that it is heavily phosphorylated at a specific phase
of the transcription cycle (3, 6). RNAP II containing an unmodified CTD
is referred to as RNAP IIA, whereas RNAP II containing a
hyperphosphorylated CTD is referred to as RNAP IIO. The largest subunit
of RNAPs IIA and IIO is designated IIa and IIo, respectively. Although
it has not been possible to map or quantitate the number of sites
phosphorylated in vivo, the number appears to be in excess
of 50 (7). Serine is the predominant site of phosphorylation with a low
level of phosphorylation on threonine and tyrosine (6, 8, 9).
RNAPs IIA and IIO have distinct roles in the transcription cycle. It is
now generally accepted that RNAP II containing an unphosphorylated CTD,
namely RNAP IIA, assembles into a preinitiation complex on the promoter
(10, 11, 12, 13). Presumably, protein-protein interactions mediated by the
unphosphorylated CTD play a role in the positioning of RNAP II at the
start site of transcription. Phosphorylation of the CTD is catalyzed by
a CTD kinase that stably associates with the preinitiation complex.
Transcript elongation is catalyzed by RNAP IIO (6, 14, 15). Therefore,
phosphorylation of the CTD accompanies the transition of RNAP II from a
preinitiation complex to a stable elongation complex. Although CTD
phosphorylation is temporally correlated with promoter clearance and
thought to be a prerequisite to the formation of a stable elongation
complex, the precise role of CTD phosphorylation remains obscure. The
idea that phosphorylation of the CTD at multiple sites serves to
disrupt interactions between the unmodified CTD and proteins necessary
for the formation of a stable preinitiation complex remains an
attractive possibility. Upon completion of the transcript, RNAP IIO
must be dephosphorylated by CTD phosphatase to regenerate RNAP IIA and
complete the cycle. The transcription cycle of RNAP II is schematically
represented in Fig. 2.
Role of CTD in Preinitiation Complex Formation and in Mediating
Activity of Transcriptional Regulators To understand the involvement of the CTD in assembly of the
preinitiation complex, it is necessary to consider the complex array of
proteins that participate in the early phase of transcription. Assembly
of a preinitiation complex and the initiation of transcription are
dependent on the presence of multiple general transcription factors
(GTFs) (16, 17). These factors, designated TFIIA, -IIB, -IID, -IIE,
-IIF, and -IIH, in addition to RNAP II are sufficient to support a
basal level of transcription from a variety of eukaryotic promoters.
Although this complement of factors is sufficient to support
transcription in reconstituted systems, additional proteins appear to
be involved in vivo. An important clue that additional
proteins are required came from the analysis of second site mutations
that suppress the conditional phenotype of CTD truncation mutants (18,
19). These SRB genes (suppressors of RNA polymerase B)
encode proteins that are involved in transcription and interact with
RNAP II (20).
Recently, a holoenzyme form of RNAP II has been described in yeast that
is comprised of the core enzyme, the GTFs TFIIB, TFIIF, TFIIH, the
products of all nine SRB genes, GAL11, SUG1, and components
of the SWI/SNF complex (19, 20, 21, 22). The SWI/SNF complex is a general
transcriptional regulator involved in chromatin remodeling. A second
form of the yeast holoenzyme has been described that also includes the
global transcriptional regulators Sin4 and Rgrl but apparently lacks
TFIIB, TFIIH, and the SWI/SNF complex (23, 24). The difference in
holoenzyme composition may arise from different methods of purification
that lead to the loss of specific components of the holoenzyme or from
differences in either growth conditions or strains of yeast.
Alternatively, multiple forms of the holoenzyme may exist. The
holoenzyme differs functionally from core RNAP II in that it is
responsive to transcriptional regulators in in vitro assays.
The multiprotein complex containing SRBs and certain GTFs is stable in
the absence of RNAP II and has been termed the mediator (19, 24). The
mediator appears to associate with core RNAP II via direct interactions
with the CTD (24). This observation is consistent with early results,
which indicate that the CTD plays an essential role in mediating the
response to various transcriptional regulators (25, 26, 27). The mammalian
holoenzyme, although less well characterized, is reported to contain
the GTFs, TFIIE, TFIIF, and TFIIH, in addition to SRB homologues and
proteins involved in DNA repair (56). The human RNAP II holoenzyme is
comprised of approximately 80 polypeptides, only some of which have
been identified.
The discovery of holo-RNAP II has caused a reconsideration of how
preinitiation complexes might assemble on the promoter. Analysis of
transcription in reconstituted reactions indicates that preinitiation
complexes can assemble by the sequential and ordered association of
individual GTFs and RNAP II with the promoter (see Fig. 2A).
Alternatively, a macromolecular complex containing multiple GTFs, SRBs,
and core RNAP II can assemble independent of the promoter and bind
directly to DNA (see Fig. 2B). It is not yet possible to
distinguish which reaction scheme more closely resembles how
transcription complexes form in vivo. However, in either
case, the CTD likely plays a critical role by mediating the interaction
of core RNAP II with the factors necessary for preinitiation complex
assembly and response to transcriptional regulators. Since neither RNAP
I nor RNAP III must integrate the input from such a diverse array of
regulatory proteins, the involvement of the CTD in mediating the input
from multiple regulators could in part account for the fact that only
RNAP II contains a CTD.
A curious feature of the CTD is its differential involvement in
transcription from different promoters. In vitro
transcription from the adenovirus-2 major late promoter, a
TATA-containing promoter, is not dependent on the CTD whereas
transcription from the murine dihydrofolate reductase promoter, a
TATA-less promoter, is dependent on the CTD (13). The CTD appears to
play a direct role in the recruitment of RNAP II in that a CTD-less
RNAP II (RNAP IIB) does not assemble into a preinitiation complex on
the dihydrofolate reductase promoter. The requirement for the CTD
appears to correlate with the absence of a TATA element and may reflect
a fundamental difference in the way transcription complexes assemble on
different promoters (28).
Identification of Proteins That Interact with the Unphosphorylated
CTD Critical to our understanding of CTD function is an identification
of proteins that make direct contact with the CTD and an understanding
of how these interactions are influenced by phosphorylation of the CTD.
The fact that mutations in SRB genes can restore wild-type
phenotype to cells containing CTD truncations indicates that both the
CTD and SRBs are involved in the same functional process. Furthermore,
the mediator, which is thought to interact with RNAP II via the CTD,
contains multiple SRBs. Although SRBs are prime candidates for
CTD-interacting proteins, a direct biochemical interaction has not been
reported. The CTD has, however, been shown to interact directly with
TATA binding protein, the TATA binding subunit of TFIID (29). Protein
cross-linking experiments have also established that the 74-kDa subunit
of TFIIF and the 34-kDa subunit of TFIIE interact with the C terminus
of the CTD (30). The CTD is an extended molecule and can potentially
form interactions with multiple proteins.
Role of CTD Phosphorylation in Establishment of
Elongation-competent Transcription Complex The finding that phosphorylation of the CTD prevents RNAP II from
assembling into a preinitiation complex and that there is a temporal
relationship between promoter clearance and CTD phosphorylation led to
the idea that phosphorylation is the trigger that releases RNAP II from
the initiated complex. However, it is now clear that transcription from
at least some promoters in defined in vitro systems is not
dependent on CTD phosphorylation (31, 32). In less defined systems,
transcription appears to be dependent on CTD kinase activity suggesting
that CTD phosphorylation may be obligatory in vivo (33).
Experiments have not been reported that would distinguish between a
requirement based on the physical release of RNAP II from the initiated
complex and a requirement for a phosphorylated CTD to establish a
stable elongation complex. For example, in the latter case the highly
phosphorylated CTD may destabilize nucleosomes, thereby facilitating
the progression of RNAP II along the DNA template. Therefore, the
possibility exists that CTD phosphorylation plays no direct role in the
initiation process but is temporally correlated with initiation because
it is essential for the formation of a competent elongation
complex.
This idea is consistent with the finding that transcription complexes
paused near the transcriptional start site on a number of
Drosophila genes contain RNAP IIA (34). The induction of
transcription and the release of RNAP II from the paused complex
correlate with phosphorylation of the CTD. One possibility is that RNAP
II is still tethered to proteins associated with the promoter by an
extended CTD and phosphorylation triggers promoter clearance.
Alternatively, RNAP II interactions with the promoter may have been
disrupted, and phosphorylation is necessary to generate an
elongation-competent form of the enzyme. Finally, the possibility that
RNAP II was phosphorylated at the time of transcript initiation and
subsequently dephosphorylated, resulting in a paused complex, cannot be
excluded. An important question is whether or not the phosphate
incorporated into the CTD during initiation turns over during
transcript elongation. Interestingly, the establishment of a stable
elongation complex in Drosophila is dependent on protein
kinase activity as indicated by the observation that the production of
long transcripts is prevented by the protein kinase inhibitor DRB
(5,6-dichloro-1- The CTD may also play a role in transcription-coupled nucleotide
excision repair. Of special interest is the association of multiple DNA
repair activities with CTD kinase in the general transcription factor
TFIIH (38, 39, 40, 41). The observation that TFIIE and TFIIF interact with the
unphosphorylated CTD and that TFIIE interacts directly with TFIIH
provides a mechanism for the recruitment of TFIIH to RNAP II paused at
DNA lesions (30, 42). Since transcript elongation is catalyzed by RNAP
IIO, according to this model, an early step in repair would be
dephosphorylation of the CTD. A CTD phosphatase has recently been
purified from HeLa cells and shown to have regulatory properties
consistent with such a function (43, 44). The subsequent recruitment of
TFIIE and TFIIH to paused RNAP IIA would facilitate repair of the
lesion and rephosphorylation of the CTD to regenerate an
elongation-competent form of RNAP II.
CTD Kinases and CTD Phosphatase A multiplicity of protein kinases actively phosphorylates the CTD
of RNAP II or synthetic peptides containing the consensus repeat
in vitro (3). However, it has been difficult to establish
which of these enzymes phosphorylate RNAP II in vivo. A CTD
kinase associated with TFIIH has emerged as a strong candidate for a
physiological CTD kinase (38, 41, 45). This idea is supported by
several observations. CTD kinase is intrinsic to TFIIH, a factor that
appears to be involved in promoter clearance and hence functions in the
transcription cycle at the time of CTD phosphorylation. The CTD kinase
associated with TFIIH has recently been identified as the
cyclin-dependent kinase (Cdk) MO15/Cdk-7 in vertebrates
(46, 47) and KIN28 in yeast (38). KIN28 is required for RNA synthesis,
and RNAP II phosphorylation is dramatically reduced at the restrictive
temperature in a kin28-ts mutant (48). TFIIH from yeast has
been fractionated into two forms, one involved in transcription and one
in nucleotide excision repair (41, 45, 49). The TFIIH core is comprised
of five subunits including RAD3, TFB1, and SSL1. The form that
functions in transcription, designated holo-TFIIH, consists of the core
in association with SSL2 and the two subunits of the TFIIH-associated
CTD kinase, designated TFIIK (50).
A second CTD kinase known to assemble into the preinitiation complex is
a cyclin-dependent kinase comprised of SRB10 and SRB11
(51). Although the in vitro phosphorylation of holo-RNAP II
containing a srb10 mutant enzyme is reduced greater than
10-fold, the in vitro transcriptional activity of the mutant
enzyme is unchanged. Nevertheless, the finding that the SRB10/11 kinase
is essential for transcriptional activation by galactose in yeast
suggests that this kinase plays a role in transcriptional regulation
in vivo.
Multiple CTD kinases appear to be involved in the phosphorylation of
RNAP II in vivo. This idea is supported by the observation
that disruption of the largest subunit of a yeast CTD kinase,
designated CTK1 and distinct from KIN28, results in a diminished level
of RNAP II phosphorylation (52, 53). Therefore, RNAP II phosphorylation
is diminished by a disruption in the activity of either KIN28 or CTK1.
The possibility that certain putative CTD kinases function in
vivo to regulate the activity of other protein kinases that
phosphorylate the CTD cannot be excluded. Finally, the observation that
the CTD can be phosphorylated on tyrosine suggests that multiple CTD
kinases function in vivo (8). The physiological significance
of multiple CTD kinases is not known. One possibility is that
phosphorylation of the CTD plays an essential role in transcription,
and redundancy has been built into the enzymes that catalyze this
reaction. It is also possible that different promoters utilize
different protein kinases and/or different protein kinases function at
specific times in the transcription cycle. Finally, the observation
that a unique form of RNAP IIO appears to be recruited to discrete
nuclear domains when transcription is inhibited suggests that a
specific CTD kinase(s) may influence the subnuclear localization of
RNAP II (54).
A CTD phosphatase has been purified from a HeLa cell transcription
extract and appears to selectively dephosphorylate the CTD of RNAP IIO
(43, 44). The regulation of CTD phosphatase activity is complex and
appears to involve an interaction of CTD phosphatase with a docking
site on RNAP II that is distinct from the CTD (44). Furthermore, the
activity of CTD phosphatase is stimulated by TFIIF, and the stimulatory
activity of TFIIF is inhibited by TFIIB. These properties of CTD
phosphatase are, therefore, consistent with the idea that it functions
to dephosphorylate RNAP IIO upon completion of a transcript, thereby
regenerating RNAP IIA for preinitiation complex formation (see Fig. 2).
TFIIF is known to directly interact with RNAP II and to play a role in
the recruitment of RNAP II to the preinitiation complex. Accordingly,
the association of TFIIF with RNAP II upon completion of the transcript
would stimulate the dephosphorylation reaction (see Fig. 2). Finally,
TFIIB may suppress the stimulatory activity of TFIIF in the
preinitiation complex, thereby preventing a futile cycle of CTD
phosphorylation-dephosphorylation. Regulating access to the docking
site on RNAP II by which CTD phosphatase gains access to the CTD may be
important in regulating the dephosphorylation of RNAP II during the
elongation phase of transcription.
Potential Regulatory Significance of CTD Phosphorylation Since RNAP IIA and IIO have distinct roles in the transcription
cycle, CTD kinases and CTD phosphatase can act as positive or negative
regulators of transcription depending on the point in the transcription
cycle at which they function. For example, phosphorylation of the CTD
concomitant with transcript initiation might stimulate transcription
whereas phosphorylation of free RNAP II would reduce the amount of RNAP
IIA available for recruitment to the promoter and hence inhibit
transcription. Conversely, CTD phosphatase that dephosphorylates RNAP
II in the initiated or elongation complex may well inhibit
transcription whereas dephosphorylation of RNAP IIO upon completion of
the transcript would stimulate transcription. A major challenge is to
not only enumerate the CTD kinase(s) and phosphatase(s) that modulate
the level of RNAP II phosphorylation in vivo but to
understand how these enzymes are regulated and the consequences they
have on the activity of RNAP II at discrete steps in the transcription
cycle.
Summary and Perspectives The CTD of RNAP II is unusual with respect to both the high level
of repetition of the consensus repeat and its high level of
phosphorylation. The fact that each round of transcription is
associated with the reversible phosphorylation of the CTD is consistent
with the idea that RNAP IIA and IIO have distinct roles in the
transcription cycle. Indeed, RNAP IIA has been shown to selectively
assemble into preinitiation complexes on a number of promoters, whereas
transcript elongation has been shown to be catalyzed by RNAP IIO. The
precise role played by the unphosphorylated CTD during initiation and
the phosphorylated CTD during elongation has not been established. The
extended nature of the CTD and the multiplicity of proteins that appear
to interact with core RNAP II via the CTD suggest that a primary
function of the CTD during initiation may be to integrate the input
from multiple GTFs and transcriptional regulators. Increasing evidence
supports the idea that the phosphorylated CTD plays a positive role
during transcript elongation, possibly by facilitating the progression
of RNAP II through nucleosomes and/or mediating transcription-coupled
splicing (55). A major goal of future studies is to characterize in
detail the biochemical mechanisms that underlie the involvement of the
CTD at discrete steps in the transcription cycle.
Although a multiplicity of CTD kinases have been described, it has not
been easy to establish which of these is directly involved in the
phosphorylation of RNAP II. The results are most consistent with the
idea that multiple CTD kinases function in vivo. Apart from
a clear definition of the role of specific CTD kinases, it will be
important to know if different promoters recruit different CTD kinases
and if the recruitment of CTD kinase can be an important step in the
regulation of gene expression. Finally, the recent purification and
characterization of a CTD phosphatase suggest that CTD
dephosphorylation may also play an important role in the regulation of
gene expression. It seems clear that an understanding of CTD function
will be dependent on an understanding of the modifications that occur
within the CTD and an understanding of the regulation of the enzymes
that catalyze these modifications.
FOOTNOTES Acknowledgments I thank Shari Blevins, Delphine Gerber, Brett
Kaiser, Alan Lehman, Nick Marshall, and Tricia Marshall for critical
reading of the manuscript.
REFERENCES
Volume 271, Number 32,
Issue of August 9, 1996
pp. 19009-19012
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
MINIREVIEW:
INTRODUCTION
Temporal Relationship between Phosphorylation of CTD and
Progression of RNAP II Through Transcription Cycle
Role of CTD in Preinitiation Complex Formation and in Mediating
Activity of Transcriptional Regulators
Identification of Proteins That Interact with the Unphosphorylated
CTD
Role of CTD Phosphorylation in Establishment of
Elongation-competent Transcription Complex
CTD Kinases and CTD Phosphatase
Potential Regulatory Significance of CTD Phosphorylation
Summary and Perspectives
FOOTNOTES
Acknowledgments
REFERENCES
Fig. 1.
The primary sequence of the C-terminal domain
of the largest RNAP II subunit from mouse (5) and yeast (4). The
consensus repeat is Tyr-Ser-Pro-Thr-Ser-Pro-Ser.
Fig. 2.
Schematic representation of the transcription
cycle of RNAP II. Panel A shows a reaction scheme in which
the formation of the preinitiation complex proceeds by the stepwise
assembly of the GTFs and RNAP II onto the promoter. The CTD is
represented by a heavy wavy line. CTDP, C-terminal domain
phosphatase. Panel B shows a reaction scheme in which the
holoenzyme is formed in the absence of DNA and loaded onto the
promoter. The composition of the mediator and RNAP II holoenzyme has
not been rigorously defined, especially in mammalian cells.
Accordingly, even though specific GTFs are shown as constituents of the
mediator or holoenzyme, this is for illustrative purposes only.
-D-ribofuranosylbenzimidazole) (35, 36, 37).
Furthermore, the elongation factor P-TEFb (positive transcription
elongation factor) has recently been found to be a CTD
kinase.2 One interpretation of these results
is that CTD kinase(s) acts on RNAP II at multiple steps in the
transcription cycle. The CTD is phosphorylated at the time of
transcript initiation by a CTD kinase that stably interacts with the
preinitiation complex, most likely TFIIH. The phosphate incorporated
into the CTD may be removed during the elongation process and, if not
restored by CTD kinase, lead to RNAP II pausing. Alternatively, the act
of pausing may trigger dephosphorylation of the CTD. It will be of
considerable interest to know if phosphate turnover occurs during
transcript elongation, whether or not the rate of turnover is
gene-specific, and what the consequences of this turnover are on
pausing and termination.
1
The abbreviations used are: RNAP, RNA
polymerase; CTD, C-terminal domain; GTF, general transcription factor;
SRB, suppressor of RNAP IIB.
2
D. H. Price, personal communication.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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T. T. Nguyen, K. Cho, S. A. Stratton, and M. C. Barton Transcription Factor Interactions and Chromatin Modifications Associated with p53-Mediated, Developmental Repression of the Alpha-Fetoprotein Gene Mol. Cell. Biol., March 15, 2005; 25(6): 2147 - 2157. [Abstract] [Full Text] [PDF]
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S. E. Kong, M. S. Kobor, N. J. Krogan, B. P. Somesh, T. M. M. Sogaard, J. F. Greenblatt, and J. Q. Svejstrup Interaction of Fcp1 Phosphatase with Elongating RNA Polymerase II Holoenzyme, Enzymatic Mechanism of Action, and Genetic Interaction with Elongator J. Biol. Chem., February 11, 2005; 280(6): 4299 - 4306. [Abstract] [Full Text] [PDF]
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S. Millhouse and J. L. Manley The C-Terminal Domain of RNA Polymerase II Functions as a Phosphorylation-Dependent Splicing Activator in a Heterologous Protein Mol. Cell. Biol., January 15, 2005; 25(2): 533 - 544. [Abstract] [Full Text] [PDF]
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M. Zhou, L. Deng, V. Lacoste, H. U. Park, A. Pumfery, F. Kashanchi, J. N. Brady, and A. Kumar Coordination of Transcription Factor Phosphorylation and Histone Methylation by the P-TEFb Kinase during Human Immunodeficiency Virus Type 1 Transcription J. Virol., December 15, 2004; 78(24): 13522 - 13533. [Abstract] [Full Text] [PDF]
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M. Gerber, J. C. Eissenberg, S. Kong, K. Tenney, J. W. Conaway, R. C. Conaway, and A. Shilatifard In Vivo Requirement of the RNA Polymerase II Elongation Factor Elongin A for Proper Gene Expression and Development Mol. Cell. Biol., November 15, 2004; 24(22): 9911 - 9919. [Abstract] [Full Text] [PDF]
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