Translesion DNA Synthesis Catalyzed by Human Pol
and Pol
across 1,N6-Ethenodeoxyadenosine*
Robert L.
Levine
,
Holly
Miller
,
Arthur
Grollman
,
Eiji
Ohashi§,
Haruo
Ohmori§,
Chikahide
Masutani¶,
Fumio
Hanaoka¶, and
Masaaki
Moriya
From the
Laboratory of Chemical Biology, Department
of Pharmacological Sciences, State University of New York, Stony
Brook, New York 11794-8651, the § Laboratory of Genetic
Information Analysis, Department of Genetics and Molecular Biology,
Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan,
and the ¶ Institute for Molecular and Cellular Biology, Osaka
University, Suita, Osaka 565-0871, Japan
Received for publication, March 9, 2001
 |
ABSTRACT |
1,N6-Ethenodeoxyadenosine,
a DNA adduct generated by exogenous and endogenous sources,
severely blocks DNA synthesis and induces miscoding events in human
cells. To probe the mechanism for in vivo translesion DNA
synthesis across this adduct, in vitro primer extension
studies were conducted using newly identified human DNA polymerases
(pol)
and
, which have been shown to catalyze translesion DNA
synthesis past several DNA lesions. Steady-state kinetic analyses and
analysis of translesion products have revealed that the synthesis is
>100-fold more efficient with pol
than with pol
and that both
error-free and error-prone syntheses are observed with these enzymes.
The miscoding events include both base substitution and frameshift
mutations. These results suggest that both polymerases,
particularly pol
, may contribute to the translesion DNA synthesis
events observed for 1,N6-ethenodeoxyadenosine
in human cells.
 |
INTRODUCTION |
In the last few years, several new human DNA polymerases
(pols),1 which are likely to
be involved in translesion DNA synthesis (TLS), were discovered. This
list includes pol
(1), pol
(2, 3), pol
(4), and pol
(5). Pol
, pol
, and pol
are encoded by the
hRAD30A, hRAD30B, and DINB1
genes, respectively. These new pols form a Rad30/UmuC/DinB/REV1
superfamily (2, 3, 6). Pol
consists of two gene products: hREV3
containing pol activity and hREV7 with an unknown function (5). In
general, these pols catalyze TLS more efficiently than previously known pols. They synthesize DNA in a distributive manner and tend to show
lower replication fidelity than other pols such as pol
, pol
,
and pol
when unmodified DNA is used as a template (7-10).
There are several pieces of evidence for the involvement of human pol
and pol
in TLS in vivo (5, 11-13). Although the involvement of human pol
or pol
has not yet been established in vivo, the Escherichia coli homologue of pol
, pol IV, has been shown to play a role in TLS in vivo
(14). Pol
, which is missing in xeroderma pigmentosum variant cells
(13, 15), is shown to catalyze efficient TLS across the
cis-syn cyclobutane thymine-thymine dimer
by inserting two dAMPs opposite the lesion (16). Therefore, the cancer
proneness of xeroderma pigmentosum variant patients is thought to be
caused by the lack of accurate TLS across this and/or other UV photo
products. Pol
also catalyzes TLS across other DNA lesions such as
cisplatin G-G intrastrand cross-link (16), acetylaminofluorene-dG (16),
and 8-oxodeoxyguanosine (17) with relatively high fidelity. On the
other hand, TLS across (+)-trans-anti-benzo[a]pyrene-N2-dG
is reported to be error-prone (18). Pol
is also shown to conduct
TLS across an abasic site (19, 20), acetylaminofluorene-dG (19,
20),
(
)-trans-anti-benzo[a]pyrene-N2-dG (20), and 8-oxodeoxyguanosine (20).
Based on these findings, we are motivated to study the efficiency and
fidelity of TLS catalyzed by these novel pols across 1,N6-ethenodeoxyadenosine (
dA) to probe the
in vivo TLS mechanism. We have shown that
dA is miscoding
in simian and human cells by inducing
dA
T,
dA
G, and
dA
C (21, 22). This adduct is produced in animals exposed to vinyl
compounds such as the human carcinogen vinyl chloride. Surprisingly,
this adduct is also found in unexposed animals and humans with
lipid peroxidation products being the suspected source of this adduct
(23). Our in vitro primer extension studies indicate that
pol
catalyzes TLS more efficiently than pol
and that both pols
catalyze error-free and error-prone TLS.
 |
MATERIALS AND METHODS |
Materials--
[
-32P]ATP was purchased from
Amersham Pharmacia Biotech. Human pol
and pol
were purified as
described (13, 19). Pol
was purified to apparent homogeneity from
calf thymus (24). Human proliferating cell nuclear antigen (PCNA) was a
generous gift from Paul Fisher (State University of New York, Stony
Brook, NY). T4 polynucleotide kinase and EcoRI were
purchased from New England Biolabs. Ultrapure deoxyribonucleic acid
triphosphates were purchased from Roche Molecular Biochemicals.
DNA Substrates--
Oligonucleotides were purchased from
Oligos Etc. (Wilsonville, OR) or synthesized in the laboratory of
Francis Johnson (State University of New York, Stony Brook, NY).
Oligomers were purified by electrophoresis on a 20% polyacrylamide gel
containing 7 M urea, detected by UV shadowing, excised from
the gel, eluted from gel slices, and desalted using a SEP-PAK C18
cartridge (Waters). Purified oligonucleotide primers were labeled at
the 5' end with [
-32P]ATP and T4 polynucleotide
kinase. Primers were annealed to templates by mixing at a 1:1.2 molar
ratio in 10 mM Tris-HCl (pH 7.5), 1 mM EDTA,
and 100 mM NaCl by heating to 80 °C followed by slow cooling. For primer extension and standing start kinetic studies (25)
of nucleotide insertion and extension, the 32P-labeled
primers (5'-GTTCTAGCGTGTAGGT, 5'-GTTCTAGCGTGTAGGTAT, and
5'-GTTCTAGCGTGTAGGTATN (where N = A, C, G, or T)) were annealed to
a 28-mer template (5'-CTGCTCCTCXATACCTACACGCTAGAAC (where X = dA
or
dA)), generating substrates 1, 2, and 3, respectively.
To quantify various TLS products, the 38-mer template
(5'-CATGCTGATGAATTCCTTCXCTACTTTCCTCTCCATTT (where X = dA or
dA; EcoRI site shown in bold)) was annealed to the
32P-labeled primer (5'-AGAGGAAAGTAG), yielding substrate 4 (Fig. 2).
Primer Extension Assays--
Each reaction mixture (10 µl)
contained 40 nM substrate 1 and 100 µM dNTPs.
Reactions with pol
(1) or pol
(19) contained 40 mM
Tris-HCl (pH 8.0), 60 mM KCl, 5 mM
MgCl2, 10 mM dithiothreitol (DTT), 2.5%
glycerol, and 250 µg/ml bovine serum albumin (BSA). Reactions with
pol
contained 7 ng/µl PCNA, 40 mM Bis-Tris (pH 6.8), 6 mM MgCl2, 2 mM DTT, 4%
glycerol, and 40 µg/ml BSA. Pol
was diluted in 20 mM
potassium phosphate (pH 7.5), 0.3 M KCl, 0.1 mM
EDTA, 0.1 mg/ml BSA, 1 mM DTT, and 50% glycerol. Pol
was diluted in 10 mM Tris-HCl (pH 7.4), 0.3 M
KCl, 1 mM EDTA, 0.2 mg/ml BSA, 1 mM DTT, and
50% glycerol. Pol
was diluted in 40 mM Bis-Tris (pH
6.8), 1 mM DTT, 0.2 mg/ml BSA, and 10% glycerol. Reactions
were initiated by adding enzyme and were incubated at 37 ± 1 °C for 10 min (pol
or pol
) or 30 ± 1 °C for 30 min (pol
). Reactions were stopped by adding 10 µl of 95%
formamide dye mixture (95% formamide, 10 mM EDTA, 0.001%
xylene cyanol, and 0.001% bromphenol blue), and then the mixture was
heated to 95 °C for 5 min. Aliquots (1 µl) were subjected to
electrophoresis in a denaturing 20% polyacrylamide gel.
Kinetic Studies of Nucleotide Insertion and
Extension--
Standing-start reactions (25) (10 µl) contained 40 nM substrate 2 or 3 (substrate 2 for insertion analysis and
substrate 3 for extension analysis), 0-2 mM dNTP(s), and a
reaction buffer (see above). Initiation and termination of reactions
were conducted as described above. Aliquots (1 µl) were subjected to
electrophoresis in a denaturing 20% polyacrylamide gel.
Data Analysis--
Integrated gel band intensities were measured
using a PhosphorImager and ImageQuant software (Molecular Dynamics).
Nucleotide incorporation parameters were determined (25). Less than
20% of the primers were extended in these steady-state kinetic
analyses, ensuring single-hit kinetics (26). Values for the
Michaelis-Menten constant (Km) and
Vmax for incorporation opposite dA and
dA
were obtained by least squares nonlinear regression to a rectangular
hyperbola. kcat was calculated by dividing
Vmax by the enzyme concentration. The frequency
of insertion (Fins) and extension
(Fext) were calculated using the equation
Fins or ext = (kcat/Km)adduct/(kcat/Km)control
(25). Standard errors derived from the curve-fitting are included.
Analysis of TLS Products--
DNA synthesis reaction mixtures
(10 µl) contained 50 nM substrate 4, 100 µM
dNTPs, the appropriate buffer (see above), and enzyme (1.5 units of pol
, 36 fmol of pol
, or 56 fmol pol
) were incubated at 23 ± 1 °C for 15 min and then 37 ± 1 °C for 45 min (27).
Reactions were stopped by adding 10 µl of a formamide dye mixture and
heating to 95 °C for 5 min. Samples were subjected to
electrophoresis in a denaturing 20% polyacrylamide gel (35 × 42 × 0.04 cm). Full-length products were extracted from the gel
and annealed to a complementary 38-mer. The annealed products were
digested with EcoRI (100 units) for 1 h at 30 °C and
then 1 h at 15 °C. This digestion generates
32P-labeled 18-mers from the fully extended products. The
products were separated in a two-phase polyacrylamide gel (15 × 72 × 0.04 cm) (27). This method allows the separation of four
base substitution products and frameshift products.
The DNA template of substrate 4 is different from the template of
substrates 1, 2, and 3 in the DNA sequence surrounding
dA. The
sequence context used in the template of substrates 1, 2, and 3 is
identical to that used in miscoding studies in human cells (22). It was
not possible to separate various TLS products by the method described
above when this sequence context was employed. Therefore, we used the
sequence (substrate 4) that has been shown to permit separation of
various TLS products by gel electrophoresis (27).
 |
RESULTS |
DNA Polymerase Activity on Control and
dA-Modified
Templates--
Pol
, pol
, and pol
/PCNA were assayed for
polymerase activity on both unmodified and
dA-modified templates.
The primer (substrate 1; Fig.
1A) allowed the addition of
two nucleotides before encountering the adduct. Although all three pols
were capable of synthesizing across
dA (Fig. 1, B and
C), this lesion posed a much stronger block to pol
than
to pol
and pol
when compared with the control templates. A very
small amount of the full-length product was generated by pol
only
when PCNA was added to the reaction mixture (compare lanes
10 and 11 with lane 12 in Fig. 1B), revealing the enhancing role for PCNA in TLS. Pol
seems to catalyze TLS more efficiently than pol
.

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Fig. 1.
Translesion DNA synthesis catalyzed by DNA
polymerases. A, template-primer (substrate 1) used in
B and C. B, calf thymus pol (0 (lanes 1 and 7), 0.09 (lanes 2 and
8), 0.19 (lanes 3 and 9), 0.38 (lanes 4 and 10), and 0.75 units (lanes
5, 6, 11, and 12)) was incubated
with substrate 1 (where X = dA in lanes 1-6
and X = dA in lanes 7-12) containing
5'-32P-labeled primer in a 10-µl reaction mixture at
30 °C for 30 min. Lanes 1-5 and 7-11
contained 70 ng of human PCNA. C, human pol (0 (lanes 1 and 6), 0.29 (lanes 2 and
7), 1.5 (lanes 3 and 8), 7.3 (lanes 4 and 9), and 36.3 fmol (lanes
5 and 10)) or pol (0 (lanes 11 and
16), 0.25 (lanes 12 and 17), 1.2 (lanes 13 and 18), 6.2 (lanes 14 and
19), and 31 fmol (lanes 15 and 20))
was incubated with the substrate 1 (where X = dA in
lanes 1-5 and 11-15 and X = dA in lanes 6-10 and 16-20) containing
5'-32P-labeled primer in a 10-µl reaction mixture at
37 °C for 10 min.
|
|
Kinetic Studies of Nucleotide Incorporation and Extension--
To
determine the efficiency and fidelity of TLS catalyzed by pol
and
pol
, we first determined steady-state kinetic parameters (Km and kcat) for nucleotide
incorporation opposite dA and
dA using substrate 2. The internal 13 nucleotides (5'-CTCCTCXATACCT) of this template are identical to those
used in the miscoding studies in human cells (22). The kinetic data
(Fins) indicate that pol
incorporates a
nucleotide opposite
dA more efficiently than pol
. Pol
inserts the correct dTMP opposite
dA twice as efficiently as dAMP
and dGMP and 13 times more efficiently than dCMP. This dTMP insertion
is ~68 times less efficient than that opposite dA. Similarly, pol
also inserts dTMP most efficiently opposite
dA, followed by dGMP and
then dAMP, but its efficiency is ~1000 times less than the
incorporation opposite dA. These results indicate that dTMP, the
correct nucleotide, is preferentially inserted opposite
dA by both pols.
We then determined steady-state kinetic parameters for nucleotide
extension from four different 3' termini located opposite dA or
dA
using substrate 3. The kinetic data (Fext)
indicate that pol
extends from all the termini more efficiently
than pol
. Pol
extends the primer with the correct dTMP terminus more efficiently than the other three termini when the modified template was used. This extension from the dTMP terminus is ~55 times
less efficient than that from the dTMP terminus located opposite dA. In
experiments using pol
, the efficiency of extension from the 3'
terminus followed the order of dAMP > dGMP > dTMP > dCMP, indicating that unlike pol
, the incorrect pairings are extended better than the correct
dA:T pairing.
Based on these insertion and extension kinetic parameters, the relative
efficiency of TLS was determined by multiplying
Fins and Fext. The
results indicate that pol
catalyzes TLS across
dA more
efficiently than pol
. With pol
, TLS with
dA:T is dominant,
and its efficiency is 3.0, 4.4, and 45 times greater than TLS with
dA:A,
dA:G, and
dA:C, respectively. The same analysis for pol
shows that the efficiency of TLS with
dA:T is 2.1 and 2.7 times
greater than TLS with
dA:A and
dA:G, respectively. These results
indicate that accurate TLS is dominant but not exclusive with both pols.
Miscoding Specificity of
dA--
Because steady-state kinetic
analysis includes only one of four dNTPs in the reaction mixture, and
frameshift mutations are not detected, we determined the miscoding
specificity of
dA in the presence of four dNTPs. We analyzed
polymerization products using substrate 4 (Fig.
2). Although fully extended products were observed with the unmodified template for all three pols, only pol
and pol
produced full-length products with the modified template
(data not shown). One possible explanation is that the 10-mer primer is
not long enough to accommodate both pol
and PCNA (28), and pol
alone cannot catalyze TLS as shown in Fig. 1B.

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Fig. 2.
Miscoding specificity of
dA in reactions catalyzed by pol
, pol , or pol
. The annealed primer-template complex
(substrate 4) is shown on top (where X = dA
or dA). Aliquots of the reaction mixtures were subjected to
two-phase 20% polyacrylamide gel electrophoresis. The mobilities of
the reaction products were compared with those of standard 18-mers
(lanes 1 and 7) containing dA, dC, dG, or dT
opposite the lesion and with those of standards containing one-
( 1) and two-base ( 2) deletions.
|
|
Fully extended products were digested with EcoRI and
electrophoresed in a two-phase polyacrylamide gel. When the unmodified template was used, pol
-catalyzed products showed only one band (Fig. 2, lane 2) that co-migrated with the dT marker,
indicating accurate DNA synthesis. Pol
also catalyzed faithful
synthesis (Fig. 2, lane 5). Pol
mainly catalyzed
error-free DNA synthesis, but two additional bands were also observed,
co-migrating with the dG and two-base deletion standards (Fig. 2,
lane 3), indicating that pol
produced errors on the
unmodified template. When the modified template was used, at least five
and four products were observed for pol
and pol
, respectively
(Fig. 2, lanes 4 and 6), co-migrating with the
dG, dA, dT, dC, or one-base deletion markers (Fig. 2, lanes
1 and 7). These products were quantified based on the
amount of radioactivity in the bands (Table II). Consistent with the
results of the steady-state kinetic analysis, pol
dominantly
catalyzed accurate TLS with dT on the modified template. However,
substantial amounts of products containing dA, dG, dC, or one-base
deletion were also observed. On the other hand, pol
dominantly
catalyzed TLS with one-base deletion, followed by dT, dA, and dC
incorporation. The results shown in Table II indicate that error-prone
TLS is dominant for both pols when frameshift mutations are included
and that pol
catalyzes accurate TLS more frequently than pol
,
but still more than 50% of the TLS is error-prone.
 |
DISCUSSION |
Pol
has been reported to catalyze TLS across several DNA
lesions in a relatively error-free manner (1, 16, 17). Our steady-state
kinetic analyses and the analysis of TLS products have revealed that
TLS catalyzed by pol
across
dA, like the benzo[a]pyrene dG
adduct (18), is significantly erroneous. Although accurate TLS with
dTMP insertion opposite
dA is predominant, pol
also frequently
catalyzed erroneous TLS, causing base substitutions and frameshift
mutations (Tables I and II and Fig. 2).
Pol
catalyzes TLS across several DNA lesions in relatively
error-free and error-prone manners (19, 20). Our steady-state kinetic analysis shows that pol
preferentially incorporates dTMP, followed by dAMP, opposite
dA (Table I). The product analysis
experiment (Table II and Fig. 2),
however, has revealed that one-base deletion events were dominant
followed by dTMP insertion products, indicating that pol
-catalyzed
TLS is also erroneous. Neither pol
nor pol
can be characterized
as simply error-free or error-prone polymerases.
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Table I
Kinetic parameters for nucleotide insertion and chain extension
catalyzed by pol and pol
ND, not determined.
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Table II
Miscoding properties of dA in reactions catalyzed by pol , pol
, or pol
Numbers represent amounts of products expressed as a percentage of a
total amount of fully extended products. 1, one-base
deletion; 2, two-base deletion.
|
|
The overall efficiency of TLS, determined by
Finc × Fext, for A:
dA
and G:
dA is similar for both pols: 9.0 × 10
5
versus 6.1 × 10
5 for pol
and
1.5 × 10
5 versus 1.2 × 10
5 for pol
(Table I). However, analysis of TLS
products shows that dA incorporation is preferred to dG by both pols:
19.8% dA versus 9.1% dG for pol
and 18.8% dA
versus 2.9% dG for pol
(Table II). It is likely that
some dGMP incorporated opposite
dA misaligned (Fig.
3, step 3) to generate a
one-base deletion, whereas dAMP incorporation does not cause this
misalignment. Accordingly, dAMP incorporation opposite
dA leads to a
base substitution, whereas dGMP incorporation results in both a base
substitution and a one-base deletion. Another mechanism envisioned is
"dNTP-stabilized misalignment," which was observed for pol
in
TLS across abasic sites (29). According to this mechanism, the
slippage event occurs first, causing
dA to be extrahelical
(step 2), and the incoming dGTP stabilizes this misalignment
(step 4). Continuous extension from this terminus results in
a one-base deletion (step 5), whereas realignment
(step 7) and extension (step 8) result in a base
substitution. The hallmark of the dNTP-stabilized misalignment mechanism is the relatively low Km for dNMP
insertion at the terminus opposite a DNA lesion, which suggests that
the incorporation is actually opposite the base 5' to the lesion (29). In the insertion kinetic studies with pol
, the
Km value for dGMP insertion opposite
dA (42.7 µM) is not much different from that for dTMP insertion
opposite dA (21.4 µM) (Table I), which suggests that dGMP
is inserted opposite dC, 5' to
dA, and extension from this terminus
results in a one-base deletion (steps 2 to 4 to
5). On the other hand, with pol
the
Km value for dGMP insertion opposite
dA (126 µM) is very different from that for dTMP insertion
opposite dA (9.4 µM) (Table I). This suggests that dGMP
is incorporated opposite
dA, followed by misalignment and subsequent
extension of the primer. This is the likely mechanism for the induction
of one-base deletions (the dominant event) by pol
.

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Fig. 3.
Model for the induction of base substitutions
and one-base deletions after the incorporation of dGMP. dGMP is
inserted opposite dA (X) (step1). This
terminal dG is extended (step 6) or misaligned with dC
located 5' to X, rendering X extrahelical
(step3). Extension of the misaligned primer generates
one-base deletion (step 5). Realignment (step 7)
and extension (step 8) yields a base substitution mutation.
Misalignment is also generated by the dNTP-stabilized
misalignment mechanism (29) in which a slippage event occurs
first, causing X to be extrahelical (step 2), and
the incoming dGTP stabilizes this misalignment (step
4).
|
|
Our mutagenesis experiments (22) have shown that miscoding events
account for 10-20% of TLS in human cells. Although it is not possible
to speculate as to what extent these pols contribute to TLS in
vivo, our results suggest that if these pols are involved in TLS
in vivo, then it is likely to be error-prone. In
vivo experiments using human cells lacking these pols are
necessary to clarify this point.
 |
ACKNOWLEDGEMENTS |
We thank F. Johnson, C. Torres, and S. Shibutani for oligonucleotides used in this research.
 |
FOOTNOTES |
*
This work was supported by United States Public Health
Service Grant CA76163 (to M. M.), the Pharmaceutical Research and
Manufacturers of America Foundation (to R. L. L.), and grants from
Core Research for Evolution Science and Technology, Japan Science and
Technology Corporation (to F. H.) and the Bioarchitect Research
Project of the Institute of Physical and Chemical Research (to F. H.).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.
To whom correspondence should be addressed: Tel.:
631-444-3082; Fax: 631-444-7641; E-mail: maki@pharm.sunysb.edu.
Published, JBC Papers in Press, March 16, 2001, DOI 10.1074/jbc.M102158200
 |
ABBREVIATIONS |
The abbreviations used are:
pol, DNA polymerase;
TLS, translesion DNA synthesis;
dA, 1,N6-ethenodeoxyadenosine;
PCNA, proliferating
cell nuclear antigen;
DTT, dithiothreitol;
BSA, bovine serum
albumin.
 |
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