Mode of Inhibition of Short-patch Base Excision Repair by Thymine
Glycol within Clustered DNA Lesions*
Helen
Budworth
§ and
Grigory L.
Dianov
¶
From the
Medical Research Council Radiation and
Genome Stability Unit, Harwell, Oxfordshire OX11 0RD, United
Kingdom and the § Biochemistry Department, University of
Oxford, Oxford OX1 3QU, United Kingdom
Received for publication, November 26, 2002, and in revised form, January 6, 2003
 |
ABSTRACT |
Clustered DNA damage, where two or more lesions
are located proximally to each other, is frequently induced by ionizing
radiation. Individual base lesions within a cluster are repaired by
base excision repair. In this study we addressed the question of how thymine glycol (Tg) within a cluster would affect the repair of opposing lesions by human cell extracts. We have found that Tg located
opposite to an abasic site does not affect cleavage of this site by
apurinic/apyrimidinic (AP) endonuclease. However, Tg significantly
compromised the next step of the repair. Although purified DNA
polymerase
was able to incorporate the correct nucleotide (dAMP)
opposite to Tg, the rate of incorporation was reduced by 3-fold. Tg
does not affect 5'-sugar phosphate removal by the
2-deoxyribose-5-phosphate (dRP) lyase activity of DNA polymerase
,
but further processing of the strand break by purified DNA ligase III
was slightly diminished. In agreement with these findings, although an
AP site located opposite to Tg was efficiently incised in human cell
extract, only a limited amount of fully repaired product was observed,
suggesting that such clustered DNA lesions may have a significantly
increased lifetime in human cells compared with similar single-standing lesions.
 |
INTRODUCTION |
Numerous cytotoxic agents exert their deleterious effects via the
formation of lesions and adducts in DNA; these effects may include
oxidized purine and pyrimidine residues, abasic sites, and single and
double strand breaks. Ionizing radiation induces damage in DNA by
direct ionization and through the generation of hydroxyl radicals that
attack DNA, resulting in single strand breaks and oxidative damage to
sugar and base residues (1). Two or more DNA lesions of the same or
different nature may be produced proximal to each other on the same or
opposite DNA strands, generally within two helical turns of the DNA.
These various types of DNA damage, known as "clustered DNA
lesions," may include strand breaks containing damaged DNA termini
accompanied by multiple base lesions of varying complexity (2, 3).
Approximately 10-20% of the damage to DNA induced by ionizing
radiation is the result of thymine base oxidation and fragmentation (4). Thymine is an easily oxidized base and is frequently found as a
component of clustered lesions (2, 3). Individual base damages within a
cluster are repaired by base excision repair (BER).1 BER is a multiprotein
pathway with a broad substrate specificity that is determined by the
damage-specific glycosylases. DNA glycosylases initiate BER by
recognizing damaged or abnormal bases and cleaving the glycosylic bond
linking the base to the sugar phosphate backbone (5). The majority of
the apurinic/apyrimidinic sites (AP sites) formed are further processed
by the so-called "short-patch" BER pathway (6). In human cells this
pathway is activated by an AP endonuclease (APE1) that introduces a DNA
strand break 5' to the AP site (7). This strand break cannot be ligated
directly; therefore, DNA polymerase
(Pol
) first adds one
nucleotide to the 3'-end of the nicked AP site, and then the dRP lyase
activity of Pol
catalyzes
-elimination of the 5'-sugar phosphate
residue (8). This creates a nick containing a 3'-OH and a 5'-phosphate end that can then be sealed by the DNA ligase III-XRCC1 (x-ray cross
complementing factor 1) complex (9). These repair events result in a
single nucleotide repair patch, and this is therefore known as
short-patch BER (6).
Several groups (reviewed in Refs. 10 and 11) have studied the effects
of opposing or multiple tandem lesions on DNA glycosylases and AP
endonucleases. Studies with oligonucleotides containing synthetic
damage clusters on opposing strands and purified glycosylases/lyases indicate that both the identity of the component lesions and their relative spacing determine the repairability of the clustered DNA
lesion (12, 13). Studies have shown that DNA glycosylases can
efficiently remove one of two closely opposed base lesions generating
an abasic site. Cleavage of the AP site by AP endonuclease produces a
nick close to the remaining lesion on the opposite strand. The removal
of the remaining base lesion is thereby inhibited (reviewed in Refs. 10
and 11). Therefore, in the course of repair, clustered lesions
containing a thymine glycol opposed by damaged adenosine or an abasic
site may be converted into a lesion consisting of Tg opposite to a
5'-sugar phosphate-containing single strand break. Tg blocks
replication by the major replicative DNA polymerases
and
(14,
15); however the effect of Tg on APE1, Pol
, and DNA ligase III, key
enzymes in the major base excision repair pathway, is not known.
In this study we have used oligonucleotide duplexes containing Tg
located directly opposite to an AP site or an AP site preincised with
APE1. Using these substrates and purified human BER proteins or human
cell extracts, we characterized the effect of Tg on the repair of
clustered lesions.
 |
EXPERIMENTAL PROCEDURES |
Materials--
Synthetic oligodeoxyribonucleotides, purified by
high performance liquid chromatography, were obtained from MWG-Biotech.
[
-32P]dATP and [
-32P]ATP (3000 Ci/mmol) were purchased from PerkinElmer Life Sciences. Recombinant
human Pol
and uracil-DNA glycosylase, purified as described (16,
17), were a gift from Dr. I. Dianova. His-tagged human DNA
ligase III and human APE1 were purified on Ni2+ agarose
followed by chromatography on a phosphocellulose column and gel
filtration on Sephacryl-200.
Cell Extracts--
HeLa whole cell extracts were prepared by the
method of Manley et al. (18) and dialyzed overnight against
a buffer containing 25 mM Hepes-KOH, pH 7.9, 2 mM DTT, 12 mM MgCl2, 0.1 mM EDTA, 17% glycerol, and 0.1 M KCl. Extracts
were aliquoted and stored at
80 °C.
Substrate Labeling--
Oligonucleotides were labeled at the
5'-end with a T4 polynucleotide kinase and [
-32P]ATP.
Unincorporated nucleotides were removed on a Sephadex G-25 spin column.
Osmium Tetroxide Modification of Thymine to Thymine
Glycol--
A reaction mixture (100 µl) containing 50 µg of the
single thymine oligonucleotide
5'-GAAGAGAGGAGAGGAGAAAGGGTAGAGAGGAAGGG AAGGAGAGAA-3', 30 mM OsO4, and 2 µl of pyridine was incubated at 37 °C for 30 min and then spun through a Sephadex G-25 spin column. The presence of Tg was confirmed by the sensitivity of the
modified oligonucleotide to piperidine and by cleavage of the
Tg-containing oligonucleotide duplex with the NTH protein (data not shown).
Preparation of DNA Substrates for Excision Assay--
To prepare
the oligonucleotide duplex, 5'-end labeled oligonucleotide
5'-TTCTCTCCTTCCCTTCCTCTCTUCCCTTTCTCCTCTCCTCTCTTC-3' was annealed
with a complementary oligonucleotide containing thymine or thymine
glycol opposite to uracil. The equimolar solution of both
oligonucleotides in TE buffer with100 mM KCl was incubated at 90 °C for 5 min, and the solution was allowed to cool slowly to
25 °C. For 3'-end labeling, the uracil-containing oligonucleotide was annealed to the two nucleotide-longer complementary oligonucleotide to create a duplex with a 5'-overhanging TT-end. This duplex was incubated with a Klenow fragment of DNA polymerase I in the presence of
[
-32P]dATP. After the end-filling reaction,
unincorporated, labeled nucleotides were removed on a Sephadex G-25
spin column.
Prior to assembly of the excision reaction, the DNA substrates (500 ng,
50 pmol) were pretreated with uracil-DNA glycosylase (200 ng, 6.25 pmol) in 10 mM Hepes, pH 7.9, 1 mM EDTA, and
100 mM KCl. The reaction mixture was incubated at 37 °C
for 1 h. To generate a substrate containing preincised AP sites,
the AP-containing substrate (1 pmol) was pretreated with APE1 (0.3 pmol) in a buffer containing 45 mM Hepes, pH 7.8, 70 mM KCl, 7.5 mM MgCl2, 0.5 mM EDTA ,and 1 mM DTT for 10 min at
37 °C.
DNA Polymerase
Synthesis--
The reaction was carried out
in a reaction mixture (10 µl) that contained 45 mM Hepes,
pH 7.8, 70 mM KCl, 7.5 mM MgCl2,
0.5 mM EDTA, 1 mM DTT, 2 mM ATP, 2 mg/ml bovine serum albumin, 20 µM each of dATP,
dGTP, dCTP, and dTTP, and a [32P]-labeled oligonucleotide
substrate (5-10 ng, 0.5-1 pmol). The reaction was initiated by the
addition of Pol
at the amount indicated in the legends to Figs.
1-3. After incubation for the indicated time at 37 °C, the reaction
was stopped by addition of 10 µl of gel-loading buffer (95%
formamide, 20 mM EDTA, 0.02% bromphenol blue, and 0.02%
xylene cyanol). Following incubation at 90 °C for 3 min, the
reaction products were separated by electrophoresis in a 20%
denaturing polyacrylamide gel containing 8 M urea in 89 mM Tris-HCl, 89 mM boric acid, and 2 mM EDTA, pH 8.0.
DNA ligase III activity was measured under the same conditions as
described for Pol
synthesis reactions. To generate the DNA ligase
substrate, oligonucleotide
5'-GAAGAGAGGAGAGGAGAAAGGGTAGAGAGGAAGGGAAGGAGAGAA-3' containing thymine
or Tg was annealed with two complementary oligonucleotides to generate
an oligonucleotide duplex with a single strand break opposite to
thymine or Tg. The indicated amounts of DNA-ligase III were added to
reaction mixtures containing 1 pmol of the substrate duplex. Reactions
were incubated for 20 min at 37 °C and processed as described above.
Products were analyzed by electrophoresis on 20% denaturing
polyacrylamide gel.
dRP lyase activity of DNA polymerase
was measured under the same
conditions as described for the DNA synthesis reaction. The indicated
amounts of Pol
were added to reaction mixtures containing 1 pmol of
3'-end labeled substrate duplex with a preincised AP site, and, after
incubation for 20 min at 37 °C, abasic sites were reduced by the
addition of 2 µl of 0.5 M NaBH4 and
incubation on ice for 10 min. Reactions were processed as described
above, and the products were analyzed by electrophoresis on 20%
denaturing polyacrylamide gel.
BER Reaction with Whole Cell Extract--
The reactions were
carried out in a reaction mixture (10 µl) that contained 45 mM Hepes, pH 7.8, 70 mM KCl, 2 mM
DTT, 7.5 mM MgCl2, 0.5 mM EDTA, 2 mM ATP, 0.4 mg/ml bovine serum albumin, 20 µM
each of the indicated dNTPs, and 32P-labeled
oligonucleotide substrate (1 pmol). The reactions were initiated by the
addition of whole cell extract (5 µg) and incubated for the indicated
time at 37 °C. Reactions were stopped by the addition of 10 µl of
0.2 M EDTA and 20 µl of chloroform/isoamyl alcohol (1:24)
mixture. After centrifugation for 2 min at 16,000 × g,
10 µl of the aqueous phase was collected, and 10 µl of the formamide dye solution was added. Following incubation at 90 °C for
2-5 min, the reaction products were separated by electrophoresis in a
20% denaturing polyacrylamide gel. All experiments were repeated at
least 3-5 times, and representative gels are shown.
 |
RESULTS |
In human cells after the incision of an AP site by APE1, base
excision repair is continued by Pol
, which incorporates a single
nucleotide into the repair gap (6, 19, 20). Using an oligonucleotide
duplex substrate containing an AP site or a preincised AP site with a
5'-sugar phosphate moiety opposite Tg on the template strand (Fig.
1A), we first investigated
whether Tg located opposite to the damage would affect DNA repair
synthesis by Pol
. Surprisingly, we found that purified human Pol
(Fig. 1B) is able to incorporate the first nucleotide
opposite to Tg, although at a slower rate than on the undamaged
template. Incorporation on a Tg-containing substrate by Pol
is
reduced by ~3-fold compared with the control substrate, with 25 fmol
of Pol
per reaction (Fig. 1B); however, at higher
concentrations Pol
was more than 80% efficient. The important
question remains whether the incorporation opposite to Tg is
error-free. Using reactions containing only one of four
deoxyribonucleotide triphosphates, we next analyzed which nucleotide is
incorporated and found that incorporation by Pol
was very specific,
with the dAMP residue exclusively incorporated opposite to Tg (Fig.
2).

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Fig. 1.
Effect of thymine glycol in a repair gap on
DNA synthesis by purified Pol . A, schematic
representation of the 32P-5'-labeled (*) oligonucleotide
substrate used. The substrate was generated by incubation of the AP
site-containing duplex with APE1. pdR stands for the
5'-sugar phosphate. B, 1 pmol of the 5'-end-labeled
substrate oligonucleotide duplex containing thymine or thymine glycol
opposite to the preincised AP site was incubated for 20 min at 37 °C
with the indicated amount of Pol in conditions described under
"Experimental Procedures." After incubation, reactions were stopped
by the addition of formamide dye solution and, following incubation at
90 °C for 3 min, the reaction products were separated by
electrophoresis in a 20% denaturing polyacrylamide gel.
|
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Fig. 2.
Specificity of incorporation opposite to
thymine glycol by purified Pol . 1 pmol of the
5'-end-labeled substrate oligonucleotide duplex containing thymine
glycol opposite to the preincised AP site was incubated for 20 min at
37 °C with 25 fmol of Pol in conditions described under
"Experimental Procedures" in the presence of either dATP, dCTP,
dGTP, or TTP (20 µM). Reactions were stopped by the
addition of a formamide dye solution and, following incubation at
90 °C for 3 min, the reaction products were separated by
electrophoresis in a 20% denaturing polyacrylamide gel.
|
|
At the next step of short-patch BER, Pol
catalyzes removal of the
5'-dRP residue. To study the effect of Tg on this reaction, we
constructed a 3'-end-labeled substrate containing thymine or Tg
opposite to the preincised AP site (Fig.
3A). Removal of the dRP from
this substrate will generate an 11-mer-labeled fragment, whereas a
dRP-containing fragment will migrate slightly slower on a gel. After
reactions, all samples were treated with sodium borohydride to
stabilize the AP sites and prevent their self-degradation during
electrophoresis. Under these conditions, we found no inhibitory effect
of Tg on dRP removal by Pol
. In fact, removal of the dRP from the
Tg-containing substrate was even slightly faster than from control
substrates (Fig. 3B).

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Fig. 3.
Effect of thymine glycol on removal of the
dRP residue by Pol . A, 1 pmol of the
3'-end-labeled (*) substrate oligonucleotide duplex containing thymine
or thymine glycol opposite to the preincised AP site was incubated for
20 min at 37 °C with the indicated amount of Pol in conditions
described under "Experimental Procedures". B, after
incubation, reactions were further incubated for 10 min on ice with 0.1 M NaBH4. Reactions were stopped by the addition
of a formamide dye solution and, following incubation at 90 °C for 3 min., the reaction products were separated by electrophoresis in a 20%
denaturing polyacrylamide gel.
|
|
During the last step of BER, DNA ligase III seals the DNA ends broken
during repair. The ability of Tg to affect DNA ligase III was tested
with a substrate simulating the last step of BER, i.e. an
oligonucleotide duplex containing a single strand break opposite to
thymine or Tg (Fig. 4A). We
found only a moderate (1.5-fold) reduction of the ligation rate for a
substrate containing Tg compared with the control substrate containing
a normal thymine (Fig. 4, B and C).

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Fig. 4.
Effect of thymine glycol on DNA ligase III.
A, schematic representation of the
32P-5'-labeled (*) substrate containing a single strand
break. B, 1 pmol of the 5'-end-labeled substrate containing
thymine or thymine glycol opposite to the single strand break was
incubated for 20 min at 37 °C with the indicated amount of DNA
ligase III in conditions described under "Experimental Procedures."
After incubation, reactions were stopped by the addition of formamide
dye solution and, following incubation at 90 °C for 3 min, the
reaction products were separated by electrophoresis in a 20%
denaturing polyacrylamide gel. C, graphical representation
of the gel shown in panel B. The amount of
ligated product was determined by quantitating the amount of substrate
and product on denaturing polyacrylamide gels using PhosphorImager
analysis.
|
|
Thus, at certain enzyme concentrations, both purified Pol
and DNA
ligase III are able to catalyze repair of an AP site opposite Tg. An
important question, however, was whether the concentration of Pol
and DNA ligase III in whole cell extracts is high enough to support
efficient repair of clustered lesions containing Tg. To address this
question, we compared repair of the oligonucleotide duplexes containing
an AP site located opposite to the Tg or opposite to thymine by human
cell extracts. Tg located opposite to the AP site did not affect
cleavage of the AP site by human AP endonuclease. When incubated with
human cell extract, the AP site-containing substrate was cleaved within
30 s, generating the 22-mer 5'-labeled incision product (data not
shown). Further repair of the AP site was monitored as restoration of
the full-length 45-mer labeled product (Fig.
5A). We found that about 20%
of the Tg-containing substrate was repaired within 20 min of incubation
with cell extract in comparison to 50-60% for the thymine-containing
substrate (Fig. 5B). We thus conclude that, although Tg does
not completely block repair, and such lesions are to some degree
repairable by BER, the inhibitory effect of Tg may cause substantial
delay in the repair of clustered lesions by BER enzymes.

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Fig. 5.
Short-patch BER in whole cell extract.
A, schematic representation of the
32P-5'-labeled (*) AP site-containing ( ) oligonucleotide
substrate used. B, 1 pmol of the 5'-end-labeled
oligonucleotide duplex containing thymine or thymine glycol opposite to
the AP site was incubated for the indicated time at 37 °C with 5 µg of HeLa whole cell extract in conditions described under
"Experimental Procedures." Reactions were stopped by the addition
of EDTA and a chloroform/isoamyl alcohol mixture, and after
centrifugation for 2 min at 16,000 × g, 10 µl of the
aqueous phase was collected, and 10 µl of the formamide dye solution
was added. Following incubation at 90 °C for 2-5 min, the reaction
products were separated by electrophoresis in a 20% denaturing
polyacrylamide gel. C, graphical analysis of three
independent experiments. The amount of repaired product was determined
by quantitating the amount of substrate and product on denaturing
polyacrylamide gels using PhosphorImager analysis.
|
|
 |
DISCUSSION |
The existence of complex DNA lesions induced by ionizing radiation
has been demonstrated experimentally (2, 3, 21). Such complex lesions
may include different combinations of base lesions and/or single strand
breaks. It was previously demonstrated that clustered lesions lead to
the formation of mutations, deletions, and chromosome rearrangements
(22-25); however, very little is known about the molecular events
leading to such dramatic genetic changes. In this study we addressed
the repair of clustered lesions containing Tg. During short-patch BER,
when a single damaged nucleotide is excised by repair enzymes, the
major threat may be simultaneous damage of the complementary base, and
the presence of Tg in the repair gap may have a major impact on the
quality and the rate of repair. Nevertheless, as we demonstrate in this
study, not all BER reactions are affected to the same extent by such
damages. Incision of an AP site by APE1 as well as the removal of the
5'-sugar phosphate by the AP lyase activity of Pol
were not
affected at all, and Tg had only a moderate (1.5-fold) inhibitory
effect on the ligation reaction. However, Tg in a repair gap
significantly affected the incorporation of nucleotides by Pol
.
Although the correct nucleotide (dAMP) is incorporated, the addition of
the first nucleotide was significantly slowed by Tg, and further
incorporation was completely blocked in repair reactions reconstituted
with purified Pol
(Fig. 1B), as well as in cell extract
(Fig. 5B, right panel). This suggests
that long-patch repair, which requires incorporation of at least two
nucleotides, would not be efficient in the repair of such lesions.
Tg, when present on the DNA template strand, blocks the progression of
replication by the major replicative DNA polymerases
and
,
although a limited incorporation opposite Tg is observed (14, 15, 26).
We also found that Pol
was able to catalyze limited incorporation
opposite to Tg and that Tg does not change the specificity of
incorporation (Figs. 1B and 2). In agreement with our
findings, early studies indicated that Tg forms a reasonably stable
base pair with adenine and that the DNA sequence immediate to Tg does
not affect the specificity of incorporation by a Klenow fragment of DNA
polymerase I or by DNA polymerase
(14, 26). Theoretically, two
major known isomeric forms of Tg (5S and 5R) (27) may affect human DNA
polymerases differently. In this study, Tg was generated by direct
oxidation of the single thymine in the template DNA using osmium
tetroxide. This procedure generates 85% of the 5R isomer (28),
suggesting that the reduced rate of incorporation of dAMP opposite
Tg observed in our experiments was mainly due to the effect of this
isomer. In support of this conclusion, kinetic analyses performed by
Hanaoka and co-workers revealed that Pol
incorporates
dAMP opposite 5R-Tg about 16-fold less efficiently than on an undamaged
template (14).
8-oxoguanine and Tg are the major oxidative lesions induced by indirect
effects of ionizing radiation caused by the generation of reactive
oxygen species. Individually, those lesions are efficiently repaired by
BER (29, 30). Moreover, as we have recently shown, 8-oxoguanine within
a repair gap does not inhibit short-patch BER (31). However, as we
demonstrate here, Tg is a much more harmful lesion. When located within
a cluster, Tg causes a substantial delay in short-patch BER of the
opposing lesion. As a result of such a delay, gapped DNA would be
exposed for a longer time to the cellular milieu. Delays in the
processing of repair intermediates may cause a significant increase in
genomic instability and affect cellular resistance to ionizing
radiation (32, 33). In summary, our data suggest that clustered lesions
containing Tg are repaired slower than a single-standing lesion of a
similar type and may be partially responsible for the deleterious
effect of ionizing radiation.
 |
ACKNOWLEDGEMENTS |
We thank Dr. David Sherratt for fruitful
discussions and Dr. I. Dianova for providing reagent proteins and cell
extracts. Dr. S. Allinson is thanked for critical reading of the manuscript.
 |
FOOTNOTES |
*
This work was supported in part by European Community Grant
FIGH-CT 2002-0027.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.:
44-1235-841-134; Fax. 44-1235-841-200; E-mail:
g.dianov@har.mrc.ac.uk.
Published, JBC Papers in Press, January 8, 2003, DOI 10.1074/jbc.M212068200
 |
ABBREVIATIONS |
The abbreviations used are:
BER, base
excision repair;
AP sites, apurinic/apyrimidinic sites, abasic sites;
APE1, human AP endonuclease;
Pol
, DNA polymerase
;
dRP, 2-deoxyribose-5-phosphate;
Tg, thymine glycol
(5,6-dihydroxy-5,6-dihydrothymidine);
DTT, dithiothreitol.
 |
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