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Journal of Bacteriology, May 1999, p. 2878-2882, Vol. 181, No. 9
Department of Biology, Boston University,
Boston, Massachusetts 02215,1 and School
of Public Health, Boston University School of Medicine, Boston,
Massachusetts 021182
Received 13 July 1998/Accepted 22 February 1999
DNA-DNA interstrand cross-links are the cytotoxic lesions for many
chemotherapeutic agents. A plasmid with a single nitrogen mustard (HN2)
interstrand cross-link (inter-HN2-pTZSV28) was constructed and
transformed into Escherichia coli, and its replication
efficiency (RE = [number of transformants from
inter-HN2-pTZSV28]/[number of transformants from control]) was
determined to be ~0.6. Previous work showed that RE was high because
the cross-link was repaired by a pathway involving nucleotide excision
repair (NER) but not recombination. (In fact, recombination was
precluded because the cells do not receive lesion-free homologous DNA.)
Herein, DNA polymerase II is shown to be in this new pathway, since the
replication efficiency (RE) is higher in a
polB+ (~0.6) than in a Interstrand cross-links are likely
to be the crucial cytotoxic lesion formed by a variety of classes of
effective antitumor agents, including the mustards, of which nitrogen
mustard was the first member used and cyclophosphamide is currently the
most commonly used (13, 22, 26, 31, 40). Factors that
modulate the levels of cytotoxic interstrand cross-links, such as DNA
repair, are expected to influence the effectiveness of such agents. It has been known for many years that interstrand cross-links may be
repaired by a combination of nucleotide excision repair (NER) and
recombination, which has been most extensively studied with psoralens
(45, 46, 49). In special cases, other DNA repair pathways
may also be important for the repair of intermediates that give rise to
interstrand cross-links, for example, with BCNU [1,3-bis-(2-chloroethyl)-1-nitrosourea] (8, 16, 17,
42, 50).
Although some progress on assessing a role for interstrand cross-links
in causing cytotoxicity has been made, for example, with HN2 (1,
36, 37), much is still not known, in part because, when
cross-linking agents react with DNA, many lesions form, including
interstrand, intrastrand, and protein-DNA cross-links, as well
monoadducts. This and other factors have made it difficult to dissect
definitively the details about how these various lesions are processed
and their unique biological effects (30, 43).
To overcome such complications, we developed a general procedure to
construct a plasmid with a single DNA-DNA interstrand cross-link at a
defined genomic position (21, 38). By these methods,
inter-HN2-pTZSV28, a plasmid which contains a single nitrogen mustard
interstrand cross-link, was constructed and characterized as described
previously (4, 21, 38). Importantly, we showed that more
than ~98% of the plasmids constructed contain a single, intact
cross-link. We have shown that the nitrogen mustard moiety is attached
to N7-dG in both strands of a 5'-GNC-3' target sequence in a unique
AccI/SalI site (38). The problem of
the inherent chemical lability of N7-dG adducts was circumvented by
converting them to their corresponding ring-opened, N7-FAPY adducts,
which are stable (38).
Cells face a difficult logistical problem in the repair of interstrand
cross-links, since both DNA strands are damaged. The commonly accepted
pathway to repair interstrand cross-links involves NER to nick the
first strand, which is then replaced with DNA from a lesion-free,
homologous, sister chromosome by recombination, as demonstrated most
clearly for psoralens (45, 46, 49). The second strand is
then presumably repaired as a monoadduct by NER.
Previously, we showed that a high yield of progeny plasmids could be
derived from inter-HN2-pTZSV28 transformed into Escherichia coli, and this process was dependent on a DNA repair pathway for the interstrand cross-link in inter-HN2-pTZSV28 that included NER
(4). However, three lines of evidence argued against a role
for recombination in this repair pathway, notably that the yield of
progeny plasmids was unaffected in a We show here that DNA polymerase II (DNA Pol II) is another component
of the recombination-independent, DNA-DNA interstrand cross-link repair
pathway. To test the physiological relevance of this new pathway, we
describe the treatment of E. coli with nitrogen mustard and
conclude that it is likely the NER/DNA Pol II pathway functions in
parallel with the NER/recombination pathway in E. coli
(i.e., in circumstances where there is a lesion-free homologous
chromosome) and that these two pathways are not completely functionally redundant.
Bacterial strains and plasmids are summarized in Table
1, including several new strains. The
uvrA6 derivatives were constructed by transducing strains to
mal::Tn10 and then to
mal+ uvrA6 by using AB1886 (24) as a
donor.
0021-9193/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
DNA Polymerase II (polB) Is Involved in
a New DNA Repair Pathway for DNA Interstrand Cross-Links in
Escherichia coli
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
polB
(~0.1) strain. Complementation with a polB+-containing plasmid restores RE to
wild-type levels, which corroborates this conclusion. In separate
experiments, E. coli was treated with HN2, and the relative
sensitivity to killing was found to be as follows: wild type < polB < recA < polB
recA ~ uvrA. Because cells deficient in either
recombination (recA) or DNA polymerase II
(polB) are hypersensitive to nitrogen mustard killing,
E. coli appears to have two pathways for cross-link repair:
an NER/recombination pathway (which is possible when the cross-links
are formed in cells where recombination can occur because there are
multiple copies of the genome) and an NER/DNA polymerase II pathway.
Furthermore, these results show that some cross-links are uniquely
repaired by each pathway. This represents one of the first clearly
defined pathway in which DNA polymerase II plays a role in E. coli. It remains to be determined why this new pathway prefers
DNA polymerase II and why there are two pathways to repair cross-links.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
recA strain of E. coli. In fact, our experimental approach actually
precluded a recombination-dependent repair pathway, since the cells did not receive a lesion-free copy of the pTZSV28 plasmid. We also showed
that this recombination-independent pathway did not involve base
excision repair (BER) or several 5'
3' exonuclease activities in
E. coli (4). (In previous work we provided
arguments for why we concluded that the effects that we have been
investigating are by necessity attributable to the nitrogen mustard
interstrand cross-link located in inter-HN2-pTZSV28
[4].)
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
recA derivatives were made by transducing the
strains to (recA srlR301::Tn10)
(14). Standard genetic techniques were used (32).
TABLE 1.
Strains and plasmids
All materials and methods were identical to those described previously (4, 21, 38) except as noted below.
In brief, inter-HN2-pTZSV28, which contains a single nitrogen mustard
interstrand cross-link, was constructed as follows. A nitrogen mustard
interstrand cross-linked duplex oligonucleotide was synthesized
(38) and incorporated into the parent plasmid pTZSV28 in a
five-step procedure, and closed circular material was isolated by
cesium chloride density gradient centrifugation (21).
pTZSV28 itself was constructed from pTZ19R (ColE1 and f1 origins,
bla for ampicillin resistance and a lacZ' gene
with a polylinker) and a portion of simian virus 40 (simian virus 40 origin and the large T antigen gene). The cross-link is located in a
unique AccI/SalI site in the polylinker.
Inter-HN2-pTZSV28 was extensively characterized, notably to show that
>98% of the material contains a single, intact cross-link
(4). Inter-HN2-pTZSV28 or its non-cross-link-containing
control (C-pTZSV28) was transformed (via electroporation) in parallel
in triplicate into each of the indicated strains (Table
2) and plated in duplicate on
ampicillin-containing plates. One day later the numbers of
ampicillin-resistant colonies were determined, and the average of the
six plates is reported (Table 2).
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The survival curves after exposure to nitrogen mustard (see Fig. 2)
were generated as follows. To 1.0 ml of the indicated E. coli strains (from an overnight culture grown in Luria broth [LB]), nitrogen mustard (stored as the hydrochloride at 
80°C in a
1 M stock solution) was added (along with an identical volume of 1 M
NaOH) to give the desired final concentrations. After incubation for
1 h at 37°C, the samples were diluted (by a factor of
103 or greater) and plated (in triplicate) on LB plates.
After incubation at 37°C for ~18 h, the colonies were counted to
determine the levels of surviving colonies.
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RESULTS |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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As we had done previously (4), a bacterial
transformation assay was used to study the extent to which a single
nitrogen mustard interstrand cross-link might inhibit DNA replication. Equal amounts (~25 pg) of either inter-HN2-pTZSV28, which contains a
single cross-link, or C-pTZSV28, which is an identically constructed control plasmid that contains no cross-link, were transformed into
cells, and the number of ampicillin-resistant colonies was determined
(4). The replication efficiency (RE), i.e., the ratio of
colonies from (inter-HN2-pTZSV28/C-pTZSV28), was determined to be ca.
0.3 to 0.6 for cells proficient in all known DNA repair pathways
(reference 4 and Table 2). The RE was shown to be significantly lower in several uvrA and uvrB
strains compared to corresponding uvr+ strains
(reference 4 and Table 2), implicating NER in the repair of the cross-link in HN2-inter-pTZSV28. To simplify comparisons, it is useful to define the relative replication efficiency (RRE) as the
ratio of RE for any repair-deficient strain of E. coli versus the RE for its corresponding wild-type strain; e.g., the RRE is
0.055 for uvrA6 versus uvrA+ (Table
2), which is similar to results we obtained previously (4).
In previous work, analogous experiments excluded a role for
recombination, BER, and several 5'3' exonuclease activities in this
DNA repair pathway (4).
This recombination-independent repair was hypothesized to proceed by
UvrABC nicking one strand near the cross-link followed by the action of
a DNA polymerase (Fig. 1). A role for DNA
Pol II was evaluated, and evidence for its involvement was obtained in
that the RRE was ~0.18 (Table 2) in two different strains of E. coli that contained a deletion of a polB gene, which
was originally developed in the laboratory of Myron Goodman
(18). The repair defect in the polB strain was
complemented by the cloned polB+ gene (Table 2,
compare PFB/pBIP [RRE = 0.26] with PFB/pHC206 [RRE = 0.98]), showing that the deficiency was truly due to the polB allele and not to some other gratuitous genetic change
in the cells. No complementation was observed with the plasmid not containing the polB+ gene. In experiment 5 (Table 2), the RE was similar for a uvrA6 (0.022) versus a
uvrA polB (0.017) strain.
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To assess whether the NER/DNA Pol II pathway is physiologically
significant, the survival of E. coli cells exposed to
nitrogen mustard was determined (Fig. 2).
Cells deficient in DNA Pol II (polB) appear to be
slightly more sensitive to killing by nitrogen mustard than were
wild-type cells. In addition, a polB recA strain was
more sensitive than a recA strain.
|
]), PFB60 (
]),
FC348 (
]), B98 (
]), and PFB50 (uvrA6 [
]). Panel a shows all of
the data, whereas panel b shows the data for the latter three strains
with an expanded abscissa. Strain FC348 is strain FC40 with a
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DISCUSSION |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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NER and DNA Pol II can be involved in nitrogen mustard interstrand cross-link repair in E. coli based on the RRE values (Table 2) in uvr (0.055) and polB (0.18) strains, respectively, compared to wild-type uvr+ polB+ (1.0) strains. The hypersensitivity of polB E. coli to killing by nitrogen mustard (Fig. 2) suggests that this pathway is physiologically relevant. The fact that the RRE is similar for both uvr and uvr polB strains (Table 2) suggests that NER and DNA Pol II are in the same pathway.
We found evidence for this NER/DNA Pol II pathway only because the
commonly accepted pathway for the repair of interstrand cross-links,
which involves NER and recombination (45, 46, 49), was
precluded since the cells receiving inter-HN2-pTZSV28 in our
experiments do not receive a lesion-free piece of DNA that is
homologous to the region around the cross-link, thus making recombination impossible. These two pathways for the repair of interstrand cross-links are likely to work in parallel and are not
functionally redundant, since cells deficient in either the NER/recombination pathway alone (recA) or the NER/DNA Pol
II pathway alone (polB) were each hypersensitive to the
killing effects of nitrogen mustard (Fig. 2). (It seems most likely
that these results are attributable to killing by cross-links rather than to killing by monoadducts, although our results do not
definitively distinguish between them.) The NER/Pol II pathway for
coping with interstrand cross-links probably serves a role analogous to
the role of SOS-dependent, translesion synthesis of bulky monoadducts (20). These pathways are likely to be necessary when lesion tolerance mechanisms (notably, those involving recombinational repair)
are impossible, such as when there are closely spaced lesions in both
sister chromosomes or when a cell does not have a homologous, sister
chromosome (e.g., in late-replicating DNA).
The recA strain is more sensitive to the killing effects
of nitrogen mustard than the polB strain, suggesting that
the NER/recombination pathway probably repairs a greater fraction of
cross-links than does the NER/DNA Pol II pathway. While it is difficult
to make a rigorous quantitative comparison, we estimate that the
NER/DNA Pol II pathway appears to be responsible for repairing ~12%
of the cross-links, based upon the differences in the dose of nitrogen mustard required to kill a particular fraction of wild-type versus polB versus recA cells (Fig. 2). {The 12%
value was calculated as follows. The number of cross-links formed in
the cells is assumed to be approximately proportional to the dose of
nitrogen mustard. It is also assumed that the same number of
cross-links are responsible for reducing cell survival to the 1% level
in wild-type, polB, and recA cells, which occurs
at nitrogen mustard concentrations of 5.0, 4.4, and 0.6 mM,
respectively. The relative fraction of lesions removed by the
polB-dependent pathway is estimated as follows: (wild
type polB)/([wild type recA] + [wild type polB]) = 0.12.} The fact that the
survival curve in the polB recA strain is virtually
superimposable on the curve for the uvrA strain (Fig. 2)
suggests that NER is common to both pathways and that these are the
only two NER-dependent pathways that repair interstrand cross-links.
The NER/DNA Pol II pathways appears to be active on other cross-links, such as that with mitomycin C (unpublished observation), which may provide an explanation for an old observation that mutagenesis by certain cross-linking agents (e.g., mitomycin C, as well as malondialdehyde) actually decreases in NER-deficient strains (27, 33, 34), implying that the mutations occur during DNA repair of a lesion, probably a cross-link, perhaps via the NER/DNA Pol II pathway. Interestingly, the NER/DNA Pol II pathway does not appear to be able to act on all cross-links, notably those from psoralens (as discussed in reference 4).
The involvement of DNA Pol II in this pathway is of interest for several reasons. Although the polB gene for DNA Pol II was first identified in 1972 (11, 23), the pathway depicted in Fig. 1 represents one of the few cases where there is good evidence of a concrete role for DNA Pol II in E. coli. It has been known for some time that DNA Pol II is damage inducible as part of the SOS response, implying that it plays some role in damage management and DNA repair (6, 7, 25). However, reports have indicated that DNA Pol II appears not to participate in UV resistance (25), UV mutagenesis (25), cyclobutane dimer mutagenesis (28), repair gap UV mutagenesis in cells (12) (although it can function in vitro [48]), Weigle reactivation (28), thymine glycol mutagenesis (28), mismatch repair (28), and UVM mutagenesis (39). There is indirect evidence for DNA Pol II involvement in abasic site mutagenesis (47), although direct evidence suggests otherwise (28). Studies have shown that DNA Pol II can substitute for DNA Pol III in some aspects of E. coli replication (41), that it is important for adaptive mutagenesis (18, 19), and that it is involved in protecting cells from H2O2 toxicity (18), although its exact role in each of these processes is unclear. In summary, DNA Pol II seems not to play a role in a variety of replication and repair processes, and where there is some evidence for its involvement, the components and the details of the pathway have not been delineated.
The results presented in Table 2 clearly indicate that DNA Pol II can be involved in the pathway depicted in Fig. 1. However, the RRE in polB cells (~0.18) is higher than in uvr cells (~0.055). This implies that some polymerase in addition to DNA Pol II either is responsible for a minor fraction of the repair or can substitute for DNA Pol II, albeit less efficiently (i.e., <20%). Nevertheless, it does appear that DNA Pol II is preferred, raising the question: why does this pathway not use either of E. coli's other two DNA polymerases (i.e., Pol I or Pol III), which participate in other DNA repair pathways (20). Perhaps DNA Pol I is too error prone in the bypass of lesions (as discussed in references 29 and 30), whereas DNA Pol III, which is able to bypass lesions reasonably accurately, at least in some cases (e.g., see references 3 and 35), is too large a complex to bypass the extremely bulky lesion depicted in step 3 in Fig. 1.
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ACKNOWLEDGMENTS |
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We gratefully acknowledge Myron Goodman for having provided numerous strains and plasmids.
This work was supported by NIH grants to E.L.L. (CA49198 and CA63396) and to P.L.F. (GM54084).
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Biology, Boston University, Boston, MA 02115. Phone: (617) 353-9259. Fax: (617) 353-6340. E-mail: loechler{at}bu.edu.
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Journal of Bacteriology, May 1999, p. 2878-2882, Vol. 181, No. 9
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Copyright © 1999, American Society for Microbiology. All rights reserved.
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