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From the Bacteriophage The multiple enzymatic activities of
A ``Sliding-back'' Mechanism to Initiate TP-primed
DNA Replication It has been shown that
Structural Mapping of the Enzymatic Activities of
Figure 1:
Structure-function
studies of
It has been described that the binding of
Communication between the N-terminal
and C-terminal Domains: Coordination between Synthesis and Degradation As described before, the mutational analysis carried out
along the By
site-directed mutagenesis of In addition to the structure-function studies that are
extrapolatable to most DNA-dependent DNA polymerases, one of the main
goals of our research is the characterization of the structural basis
for the intrinsic high processivity of Attempts to obtain
Volume 271,
Number 15,
Issue of April 12, 1996 pp. 8509-8512
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
29 DNA Polymerase (*)
INTRODUCTION
A ``Sliding-back'' Mechanism to Initiate TP-primed
DNA Replication
Structural Mapping of the Enzymatic Activities of
29 DNA Polymerase
Communication between the N-terminal
and C-terminal Domains: Coordination between Synthesis and Degradation
Future Prospects
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
29 DNA polymerase, the product of the viral
gene 2, was originally characterized as a protein involved in the
initiation of 29 DNA replication based on both in vivo(1) and in vitro(2, 3, 4) studies. The cloning of gene
2(5) , the overproduction and purification of its
product(6) , and the development of an in vitro system
for complete 29 DNA replication (7) allowed the
characterization of protein p2 as the viral DNA replicase(8) .
This monomeric enzyme, with a molecular mass of only about 66 kDa,
catalyzes two distinguishable synthetic reactions: 1) DNA
polymerization, as any other DNA-dependent DNA polymerase, with
insertion discrimination values ranging from 10
to 10
and with an efficiency of mismatch elongation
10
-10-fold lower than that of a properly
paired primer terminus(9) ; 2) terminal protein (TP) (
)deoxynucleotidylation, which consists of the formation of
a covalent linkage (phosphoester) between the hydroxyl group of a
specific serine residue (Ser
) in 29 TP and 5`-dAMP,
requires the presence of divalent metal ions and is strongly stimulated
by the presence of the viral DNA replication origins. By means of this
reaction, in which the TP is acting as a primer, 29 DNA
polymerase catalyzes the initiation step of 29 DNA
replication(5, 8) . In addition to the synthetic
activities, 29 DNA polymerase has two degradative activities: 1)
pyrophosphorolysis, the polymerization reversal, whose physiological
significance is still unclear(10) ; 2) 3`-5`-exonuclease,
shown to be involved in a proofreading
function(11, 12) . This activity, kinetically
characterized using ssDNA as substrate and Mg
as
metal activator(13) , degrades processively DNA substrates
longer than six nucleotides, the catalytic constant being 500
s
. When the DNA length is reduced below 6-4
nucleotides, the 29 DNA polymerase-ssDNA complex dissociates at a
rate of 1 s.29 DNA polymerase (summarized in Table 1) allow this enzyme
to be the only polymerase involved in the replication of the 29
genome(7, 14) . Moreover, the enzyme has two intrinsic
properties: high processivity (>70 kilobases) and strand
displacement ability(15) . Based on this enzymatic potential,
complete replication of both DNA strands can proceed continuously from
each terminal priming event, without the need of synthesis of
RNA-primed Okazaki fragments and making unnecessary the participation
of accessory proteins and DNA helicases. The efficiency of the
protein-primed initiation reaction is in part guaranteed by the
previous formation of a heterodimer between TP and DNA
polymerase(16) , whereas the nucleotide specificity, as in
normal DNA polymerization, is dictated by the DNA
template(17) .
29 DNA polymerase does not start
replication at the first base of the genome but employs the second
position from the 3`-end of the template for the initial base pairing
and formation of the corresponding TP-dAMP complex at each DNA end. The
DNA ends (telomeres) are recovered by a specific mechanism, so called
``sliding-back,'' that is based on a 3`-terminal repetition
of two T residues. This reiteration permits, prior to DNA elongation,
the asymmetric translocation of the initiation product, TP-dAMP, to be
paired with the first T residue(18) . The fact that
TP-containing genomes, either from virus or linear
plasmids(7) , contain some kind of sequence repetitions at
their ends supports the hypothesis that the ``sliding-back''
mechanism could be a common feature of protein-primed replication
systems(18) . This proposal has been demonstrated in the case
of bacteriophages PRD1 from Escherichia coli and Cp1 from Streptococcus pneumoniae and in adenovirus. PRD1 DNA
polymerase initiates replication at the fourth nucleotide of the
terminal 3`-CCCC repetition (19) and Cp1 DNA polymerase at the
third nucleotide of the terminal 3`-TTT repetition, (
)the
end being recovered in both cases by a ``stepwise
sliding-back'' mechanism. Adenovirus DNA polymerase initiates
replication at the fourth nucleotide of the terminal repetition
3`-GTAGTA, followed by a preelongation step that originates TP-CAT, the
end being recovered by a ``jumping-back'' step (20) .
29 DNA Polymerase
The C-terminal Domain of
29 DNA PolymeraseDNA Polymerization
Our structure-function
studies of 29 DNA polymerase started when we found three regions
of significant amino acid similarity, shared with other DNA polymerases
from eukaryotic origin. Interestingly, these segments of similarity
served to identify putative DNA polymerases encoded by linear plasmids
from eukaryotic organisms, being also present in the DNA polymerase
from bacteriophage T4(21) . In good agreement with such a novel
eukaryotic filiation, 29 DNA polymerase and T4 DNA polymerase
were shown to be sensitive to specific inhibitors of eukaryotic DNA
polymerase 
such as aphidicolin, phosphonoacetic acid,
butylanilino-dATP, and butylphenyl-dGTP(21, 22) .
These three regions, located in the C-terminal portion of each
polypeptide (see Fig. 1A), contained the amino acid
motifs ``DXSLYP,''
``KX
NSXYG,'' and
``YXDTDS.'' The results obtained by site-directed
mutagenesis at these three motifs of 29 DNA polymerase (23, 24, 25, 26) support the
proposal that these three segments, corresponding to motifs A, B, and
C, form an evolutionary conserved polymerization active site in several
groups of nucleic acid-synthesizing enzymes (27) . Afterward,
more detailed amino acid sequence comparisons, facilitated by the
increasing number of DNA polymerase sequences available, allowed
definition of additional conserved regions and motifs belonging to the
C-terminal portion of the eukaryotic type
superfamily(28, 29) , whose general conservation among
other polymerase families is not clear at present. Two of these motifs,
``TXGR'' and ``KXY,''
have been also studied by site-directed mutagenesis in 29 DNA
polymerase(30, 31) . The mutational analysis
demonstrated that the C-terminal two-thirds of the 29 DNA
polymerase polypeptide constitutes the polymerization domain,
containing sites for interaction with the metal activator, dNTPs, and
DNA (see Fig. 1B). Thus, three aspartate residues,
invariant in all members of the eukaryotic type superfamily, were
implicated in metal binding and catalysis at the polymerization active
site(23, 25) . These 29 DNA polymerase residues,
Asp
, belonging to motif
``DXSLYP,'' and Asp
and
Asp
, belonging to motif
``YXDTDS,'' are predicted to form a
metal binding tripod, analogous to that formed by Pol I residues
Asp
, Asp
, and Glu
, by human
immunodeficiency virus-reverse transcriptase residues
Asp
, Asp
, and
Asp
(32) , and by Pol 
residues
Asp
, Asp
, and
Asp
(33, 34) . In addition, 29 DNA
polymerase residue Arg
, forming part of the
``TXGR'' motif, was also proposed
to play a role in catalysis of the polymerization
reaction(30) . Three tyrosine residues, invariant or highly
conserved in the eukaryotic type superfamily, were identified as
directly or indirectly involved in interaction with dNTPs: Tyr
(motif
``DXSLYP''(24, 25) ),
Tyr
(motif
``KXNSXYG''(24, 26) ),
and Tyr
(motif
``YXDTDS''(23) ). Several defects
such as an increased K
for dNTPs, instability of
the incorporated dNTPs, altered sensitivity to dNTP analogs, and
reduced selection of the correct dNTPs, could be measured either during
DNA polymerization or TP-primed initiation reactions. Tyr and Tyr were also involved in nucleotide binding
selection, thus playing a crucial role in the fidelity of DNA
replication(35) . Eight residues, invariant or highly conserved
in the C-terminal domain of eukaryotic type superfamily, have been
involved in binding template-primer structures (see Fig. 1B): Ser
(motif
``DXSLYP''(25) ),
Asn
, Gly
, and Phe
(motif
``KXNSXYG'' (26) ), Thr
and Arg (motif
``TXGR''(30) ), and
Lys
and Tyr
(motif
``KXY''(31) ).
29 DNA polymerase. A, relative arrangement of
the most conserved regions among prokaryotic and eukaryotic DNA
polymerases. The amino acid sequence of 29 DNA polymerase (572
amino acids) is represented by a bar, with the N terminus at
the left. Gray and filled-in regions indicate the
predicted 3`-5`-exonuclease and DNA polymerization domains,
respectively. The area in between these two domains (ct) has
been involved in the communication or cross-talk among these two
domains. Alternative nomenclature for the regions (boxed) that
contain the motifs (44) is indicated. A, B,
and C correspond to motifs that are generally conserved among
different classes of nucleic acid-synthesizing enzymes(27) . B, proposed role for individual residues forming highly
conserved N-terminal and C-terminal motifs of 29 DNA polymerase,
as defined by site-directed mutagenesis. Motifs are represented in
single-letter notation, where x indicates any amino acid.
Alternative residues for a particular position are separated by a bar. A summary of the mutational analysis carried out in
29 DNA polymerase is described in the
text.
Structural Mapping of Processive Synthesis by
A flexible subdomain of Klenow, which closes the
``primer cleft'' once the DNA is bound to it(36) ,
was proposed to be mainly responsible for the extent of processivity
required by Pol I, a repair enzyme. However, the high processivity
required for DNA replication is generally achieved by association of
the catalytic subunit with accessory proteins that reduce the rate of
dissociation of the enzyme from the DNA, relative to translocation and
further nucleotide addition. The fact that 29
DNA Polymerase29 DNA polymerase is
highly processive in the absence of any accessory protein suggests that
this enzyme must have specific binding subdomains involved in
processivity. By amino acid sequence comparisons, two large insertions
flanking the evolutionary conserved motif
``KXNSXYG'' have been
identified in 29 DNA polymerase and in other DNA polymerases
catalyzing TP-primed replication, a mechanism involving highly
processive synthesis of both DNA strands(21, 37) . The
structural mapping of the putative 29 DNA polymerase domain(s)
involved in processivity will be carried out by site-directed
mutagenesis of the most conserved residues corresponding to these two
specific insertions.29 DNA polymerase to DNA primer-template structures is largely
enhanced by the presence of metal ions known to activate DNA
polymerization(30) . This behavior suggests that metal-assisted
DNA binding could also increase the efficiency of DNA translocation,
thus favoring the processivity of 29 DNA polymerase.TP-primed Initiation
29 DNA polymerase
interacts with TP to form a very stable heterodimer as a prerequisite
in the initiation of 29 DNA replication(16) . By
extrapolation to the three-dimensional structure of the Klenow fragment
of E. coli DNA polymerase I (Pol IK) complexed with
DNA(36) , the same cleft involved in binding the
double-stranded region (primer cleft) of the replicating DNA molecule
is proposed to be also the TP-binding site. In agreement with that,
mutations at residues Thr and Arg (motif
``TXGR'') of 29 DNA
polymerase parallelly decreased the ability to bind both the TP and
template-primer DNA molecules (30) (see Fig. 1B). Moreover, recent results indicate that one of
the specific insertions, proposed to form a flexible domain that could
be involved in processivity of protein-priming DNA polymerases, appears
to have a direct role in TP binding. ()Based on our
site-directed mutagenesis analysis of 29 DNA polymerase, it can
be also concluded that protein-primed initiation and DNA polymerization
are both catalyzed at a unique active site, involving the same critical
residues and amino acid motifs generally conserved in eukaryotic type
DNA polymerases.The N-terminal Domain of
29 DNA Polymerase3`-5`-Exonuclease
Based on both amino acid
sequence similarities and site-directed mutagenesis studies in 29
DNA polymerase, Bernad et al.(38) proposed that the
3`-5`-exonuclease active site of prokaryotic and eukaryotic DNA
polymerases is evolutionary conserved, being formed by three N-terminal
amino acid segments (ExoI, ExoII, and ExoIII) that invariantly contain
the five critical residues identified in Pol IK, involved in metal
binding and 3`-5`-exonuclease catalysis (39) (see Fig. 1A). The validity of this proposal has been
confirmed in the case of other prokaryotic and eukaryotic enzymes such
as T7, T4, and herpes simplex virus DNA polymerases, E. coli Pol II, Bacillus subtilis Pol III, and cellular DNA
polymerases 
, 
, and 
from Saccharomyces cerevisiae (see an excellent review of all these mutagenesis studies by
Derbyshire et al.(40) ). A steady-state analysis of
mutants at each putative 3`-5`-exonuclease active site residue of
29 DNA polymerase (Asp
, Glu
,
Asp
, Tyr
, and Asp
)
demonstrated their role in catalysis, supporting the idea that the
geometry of the Pol I 3`-5`-exonuclease active site and the
two-metal ion mechanism proposed for this enzyme (41) can be
extrapolated to 29 DNA polymerase and the rest of proofreading
DNA polymerases(13) . In addition to the residues involved in
metal binding and catalysis at the 3`-5`-exonuclease active site,
other residues appear to be structurally and functionally conserved at
the exonuclease domain of most prokaryotic and eukaryotic DNA
polymerases. Among them, 29 DNA polymerase residues Thr
and Asn
, located at the ExoI and ExoII motifs,
respectively, act as single-stranded DNA ligands, having a critical
role in the stabilization of the frayed primer terminus at the
3`-5`-exonuclease active site (42) (see Fig. 1B).Strand Displacement
Surprisingly, the mutational
analysis of the ExoI, ExoII and ExoIII motifs of 29 DNA
polymerase showed that the intrinsic capacity to couple strand
displacement to DNA polymerization is also located in the N-terminal
domain, somehow overlapping with the 3`-5`-exonuclease active
site (9, 43) (Fig. 1A). Our model
proposed that the enzyme could make an alternative use of the ssDNA
binding site, present at the N-terminal domain, either to bind the
3`-5`-exonuclease substrate or to stabilize the interaction
between the polymerase molecule and the DNA strand to be displaced.
However, the ssDNA ligands Thr and Asn of
29 DNA polymerase seem to be specialized in the stabilization of
the editing complex, not having a role in the strand displacement
capacity of the enzyme(42) . Therefore, a dual role in
3`-5`-exonuclease and strand displacement appears to be
restricted to residues directly acting as metal ligands (see Fig. 1B), such as residues Asp and
Glu of the ExoI motif (DXE),
Asp of the ExoII motif
(NX
(F/Y)D), and Asp of the ExoIII motif (YXD), or likely
affecting the metal binding network, such as Tyr of the
ExoIII motif (YXD). These data suggest that
the interaction with the displaced strand, leading to duplex opening,
could be assisted by contacts with the divalent metal ions that hold
and orient the ssDNA substrate for exonucleolytic proofreading.Structural Independence of
A C-terminal deletion derivative of 29 DNA Polymerase
Domains29 DNA polymerase,
containing the first 188 N-terminal amino acid residues (including the
three Exo motifs), was independently expressed in E. coli cells. As expected from our hypothesis of a modular organization
of enzymatic activities in 29 DNA polymerase, analogous to that
of the Klenow fragment of DNA polymerase I, this N-terminal domain was
devoid of any synthetic activity (TP-primed initiation and DNA
polymerization) but retained 3`-5`-exonuclease
activity(44) . Recently, a N-terminal deletion derivative of
29 DNA polymerase, lacking the first 188 N-terminal amino acid
residues (among them the three Exo motifs), has been independently
expressed in E. coli cells. This C-terminal domain retained
both synthetic activities, TP-primed initiation and DNA polymerization,
but it was devoid of 3`-5`-exonuclease activity. ()
29 DNA polymerase molecule allowed demonstration of the
existence of two structurally independent domains containing the
synthetic and degradative activities of this enzyme. However, for an
effective proofreading of DNA polymerization errors, a mechanism for
coordinating DNA polymerization and DNA excision must exist, relying on
a structural and functional communication or cross-talk between the
N-terminal and C-terminal domains. The basis of this communication,
specially important in the case of processive DNA polymerases, involves
the intramolecular switching of the primer terminus between the
polymerization and 3`-5`-exonuclease active sites.29 DNA polymerase, it has been
recently demonstrated that the conserved motif
``YXG(G/A),'' located between the
3`-5`-exonuclease and polymerization domains of eukaryotic type
DNA polymerases (Fig. 1), is a DNA binding motif that plays a
role in the coordination between DNA synthesis and proofreading. ()We propose that residues Tyr
and Phe
of 29 DNA polymerase are primarily involved in the
stabilization of template-primer structures at the polymerization
active site, playing also a role in the movement (switching) of the
primer terminus between the polymerase and exonuclease active sites.
This dual role could be achieved if the ``YXG(G/A)''
motif is involved in a conformational change, triggered by the
unstabilization produced by insertion of a mismatched nucleotide. In
addition to this motif, other amino acid residues of 29 DNA
polymerase have been implicated in stabilization of the primer terminus
at both polymerization (Thr, Arg,
Lys, and Tyr) and exonuclease (Thr and Asn) active sites, playing in this case an
indirect role in the dynamics of DNA interaction required to coordinate
polymerization and proofreading.
29 DNA polymerase. To
approach this problem, we will search for specific subdomains that
could lead to a proliferating cell nuclear antigen-like topological
interaction with DNA. As it has been described for both proliferating
cell nuclear antigen (45) and the subunit of E. coli DNA polymerase III(46) , such a strong interaction would
be dissociated only when reaching a DNA end, as should be the case
after completing replication of the linear 29 DNA molecule. Of
additional interest is understanding how 29 DNA polymerase is
able to use both a protein and DNA as primers, and the dynamics of
interactions occurring at the transition between TP-primed initiation
and the elongation stage of 29 DNA replication. One of the most
intriguing questions is whether, after formation of the TP-dAMP
initiation complex, TP and 29 DNA polymerase must dissociate
either as a consequence of the special translocation step
(``sliding-back''), necessary to accommodate the newly
created primer terminus in an adequate position to accept the next
incoming dNTP, or after the synthesis of a short DNA suitable to be
used as primer.29 DNA polymerase crystals
adequate for x-ray diffraction analysis were not successful so far.
Other approaches, such as the crystallization of 29 DNA
polymerase complexed with TP, will be also explored to elucidate the
structural basis for the vast potential of this monomeric enzyme.
)))))
We thank all colleagues at the laboratory that have
contributed to the results presented in this review.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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