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Biochemistry and Biophysics |
Institute of Pharmacology and Toxicology, University of Zürich-Tierspital, CH-8008 Zürich, Switzerland [T. B., M. T. H., H. N.]; Chemistry Department, New York University, New York, New York 10003 [N. L., N. E. G.]; American Health Foundation, Valhalla, New York 10595 [S. A.]; and Institute of Toxicology, University of Mainz, D-55131 Mainz, Germany [H. K., A. S.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The metabolically activated polycyclic aromatic hydrocarbons have been
classified into bay and fjord region diol-epoxides. This distinction
indicates structural differences in the critical area of epoxide
formation, involving either a crowded fjord region or a sterically less
hindered bay region (Fig. 1
). The epoxide group in the fjord region causes a distortion from
planarity of the adjacent aromatic rings, whereas, in the case of the
bay region compounds, steric hindrance effects are less pronounced, and
the aromatic ring system remains planar (6
, 7)
. Both bay
and fjord region diol-epoxides can exist in a number of different
stereoisomeric configurations that display variable biological
activities. Among the bay region
B[a]P3
derivatives, the (+)-anti-B[a]P diol-epoxide
shown in Fig. 1
is the most genotoxic isomer in mammalian systems
(14, 15, 16)
. The biological activity of fjord region
B[c]Ph diol-epoxides also depends on their stereochemical
configuration, with the (-)-anti-B[c]Ph
diol-epoxide illustrated in Fig. 1
being the most potent isomer in
animal tumorigenesis assays (17
, 18)
. Our present study
was instigated by previous reports showing that
(-)-anti-B[c]Ph diol-epoxide, as well as
analogous metabolites of other fjord region compounds, is up to 10
times more active in inducing tumors in animals than any known bay
region diol-epoxide derivative (17, 18, 19, 20, 21)
. This exceptional
tumorigenic activity of the metabolites with sterically hindered fjord
regions relative to structurally similar compounds with unhindered bay
regions is of critical interest for understanding the mechanisms of
tumor initiation by chemical carcinogens in detail. No obvious
correlation was found between the DNA reactivity of individual
diol-epoxides stereoisomers and their known tumorigenic effects
(22
, 23)
, suggesting that their variable genotoxic potency
is influenced by the distinct molecular properties of the ultimate
adducts in DNA. In this study, we tested the hypothesis that the
genotoxicity of B[c]Ph diol-epoxides may be enhanced by
inefficient repair of the fjord region DNA adducts generated by these
particular compounds. Because induction of carcinomas in rodents by
polycyclic aromatic hydrocarbons has been shown to involve A to T
transitions in the second position of ras codon 61
(24)
, we constructed stereochemically defined
B[a]P-dA and B[c]Ph-dA adducts at the second
base of two distinct ras codon 61 contexts and measured
excision repair activity elicited by these site-specific lesions. Our
results show that human nucleotide excision repair enzymes are indeed
able to process a broad range of bay region B[a]P-dA
lesions with comparable efficiencies. However, we found that the same
excision repair system fails to remove the major fjord region
B[c]Ph-dA adducts from the tested N-ras and
H-ras codon 61 sequences.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Modified Oligonucleotides.
Site-directed B[a]P-N2-dG
lesions were obtained by reacting the 11-mer oligonucleotide
5'-CCATCGCTACC-3' or the 14-mer oligonucleotide 5'-ATACCCGGGACATC-3'
with
(±)-7ß,8
-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-benzo(a)pyrene
(racemic anti-B[a]P diol-epoxide) as described elsewhere
(26
, 27)
. The modified oligonucleotides were purified by
reverse-phase HPLC chromatography using octyldecyl silane Hypersyl
columns. To establish the stereochemical identity and purity of the
chromatographic fractions, the samples were enzymatically digested to
the nucleoside level. The stereochemistry of each modified
2'-deoxyguanosine species was established by HPLC chromatography and
circular dichroism using appropriate
anti-B[a]P-N2-dG
standards (28
, 29) .
Site-directed (+)- or (-)-trans-anti-B[a]P-N6-dA adducts in the N-ras oligonucleotide 5'-CGGACA*AGAAG-3' or in the unrelated sequences 5'-GGTCA*CGAG-3' and 5'-CTCTCA*CTTCC, as well as site-directed (+)- or (-)-trans-anti-B[c]Ph-N6-dA adducts in the N-ras oligonucleotide 5'-CCGGACA*AGAAGC-3' (the modified adenosine is indicated by the asterisk), were obtained by incorporating appropriate phosphoramidites in the automated DNA synthesizer technique (30, 31, 32) . After DNA synthesis, the modified oligonucleotides were deprotected and purified by reverse-phase HPLC (32) . The identity of individual adducts was assessed after enzymatic degradation as described previously (29 , 32) and confirmed by negative ion mode electrospray mass spectrometry (33) . Similarly, the H-ras oligonucleotides 5'-GGCCA*GGAGGAGTACAGC-3' containing a (+)-trans-anti-B[a]P-N6-dA, (-)-trans-anti-B[a]P-N6-dA, (+)-trans-syn-B[a]P-N6-dA, (-)-trans-syn-B[a]P-N6-dA, (+)-trans-anti-B[c]Ph-N6-dA, or (-)-trans-anti-B[c]Ph-N6-dA adduct (indicated by the asterisk) were synthesized using the appropriate phosphoramidites. After oligonucleotide synthesis and purification, the presence of individual adducts was established by fluorescence emission spectroscopy (30, 31, 32) . The stereochemistry of each adduct was confirmed by comparing circular dichroism spectra of the respective mononucleosides with those documented in the literature (34 , 35) .
Excision Repair Substrates.
To obtain internally labeled DNA duplexes of 139–146 bp, the modified
oligonucleotides or their unmodified controls (70 pmol) were 5'
end-labeled with [
-32P]ATP (7000
Ci/mmol; ICN Pharmaceuticals) and mixed with five other partially
overlapping oligonucleotides (100 pmol) that were phosphorylated with
cold ATP. The oligonucleotides were annealed and ligated in the
presence of T4 DNA ligase, followed by electrophoretic purification of
the full-length fragments as described previously (36
, 37)
.
Excision Assay.
Oligonucleotide excision reactions (36, 37, 38)
contained (in
25 µl) 35 mM HEPES-KOH (pH 7.9); 60 mM
KCl; 40 mM NaCl; 5.6 mM
MgCl2; 2 mM ATP; 80 µM
each of dATP, dCTP, dGTP, and TTP; 0.8 mM DTT; 0.4
mM EDTA; 3.4% (v/v) glycerol; 5 µg of BSA, 5 fmol
(75,000 dpm) of radiolabeled DNA substrate; and 50 µg (in protein
equivalents) of HeLa cell extract. After the indicated incubation times
at 30°C, reactions were stopped by the addition of SDS (0.3% w/v)
and proteinase K (200 µg/ml), followed by proteinase K digestion for
15 min at 37°C. DNA was purified by phenol-chloroform extraction and
resolved by electrophoresis in 10% polyacrylamide denaturing gels,
after which the radiolabeled excision products were visualized by
autoradiography. The relative levels of excision were determined by
densitometric analysis of oligonucleotides in the 24- to 32-mer size
range on appropriately exposed X-ray films (using a Molecular Dynamics
computing densitometer with ImageQuant software). The linearity of each
densitometric quantification was confirmed by counting Cerenkov
radiations of the corresponding gel slices.
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RESULTS |
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). Before substrate assembly, the central oligonucleotides
were labeled with [-32P]ATP at the 5' ends
such that the linear duplexes contained an internal radiolabel in the
vicinity of the damaged site (Fig. 2A
). After purification,
these double-stranded fragments were incubated in a standard HeLa cell
extract that is proficient in nucleotide excision repair activity when
supplemented with ATP and deoxyribonucleoside triphosphates (25
, 36, 37, 38)
. In this assay, human excision repair enzymes generated
radioactive oligonucleotide products that were separated from substrate
DNA by denaturing gel electrophoresis and visualized by
autoradiography. A typical reaction in human cell extracts is
illustrated in the autoradiogram of Fig. 2B
, where we
assessed excision of
B[a]P-N2-dG adducts in
the artificial sequence 5'-TCGCT-3'. As reported previously
(41)
, this comparison revealed considerable differences in
repair efficiency, but all tested stereochemical variants of the
B[a]P-N2-dG lesion were
processed by the human nucleotide excision repair system, yielding
characteristic excision products of 24–32 nucleotides (Fig. 2B
, Lanes 2–5). No excision products were
released from undamaged control substrate (Fig. 2B
,
Lane 1), although intact full-length substrate as well as
radioactive bands generated by nonspecific nuclease activity can be
observed at similar levels at the top of the gel. The repair efficiency
observed during 40-min incubations in cell extract (<10%) is
comparable with the rate of global repair in intact human cells, in
which moderately distorting DNA adducts such as cyclobutane pyrimidine
dimers have been shown to be removed with a half-life of up to 12 h (42)
. In any case, quantitative analysis of specific
24–32-nucleotide-long products by laser scanning densitometry showed
that the rare
(-)-cis-anti-B[a]P-N2-dG
lesion rather than the quantitatively more frequent
(+)-trans-anti-B[a]P-N2-dG
isomer constitutes a preferred excision repair substrate (Fig. 2C
). Therefore, this
(-)-cis-anti-B[a]P-N2-dG
adduct was used as a positive standard in subsequent repair reactions.
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, Lanes 2 and 3). In contrast to these
DNA lesions derived from B[a]P, we found that (+)- and
(-)-trans-anti-B[c]Ph-N6-dA
adducts located at the same second position of N-ras codon
61 failed to stimulate oligonucleotide excision (Fig. 3A
,
Lanes 5 and 6). We obtained identical results,
i.e., moderate excision of
B[a]P-N6-dA adducts but
no excision of the corresponding
B[c]Ph-N6-dA adducts,
when the same experiment was repeated using independent substrate and
HeLa cell extract preparations (gel not shown). As expected, no
oligonucleotide excision was observed after incubation of undamaged
control substrates in the HeLa cell extracts (Fig. 3A
,
Lane 4).
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). Thus, we found that (+)- or
(-)-trans-anti-B[a]P-N6-dA
adducts were processed with an efficiency similar to that of the
corresponding (+)- or
(-)-trans-anti-B[a]P-N2-dG
adducts of Fig. 2
. Also, quantitative evaluation of three independent
experiments confirmed the complete absence of oligonucleotide excision
in response to B[c]Ph adducts at the second position of
N-ras codon 61 (Fig. 3B
). To rule out the
possibility that the DNA preparations with
B[c]Ph-N6-dA adducts
contained a chemical contaminant that may inhibit DNA repair in a
nonspecific manner, we performed coincubation reactions in which the
actively repaired
(+)-trans-anti-B[a]P-N6-dA
adduct was mixed with equal amounts of substrate containing the
unrepaired
(+)-trans-anti-B[c]Ph-N6-dA
adduct. These coincubation experiments yielded the expected amounts of
B[a]P excision, thereby excluding the presence of a repair
inhibitor in the fractions of B[c]Ph-damaged DNA (Fig. 3B
). Also, time course experiments showed that differential
repair of B[a]P and B[c]Ph adducts in
N-ras codon 61 is already visible during early stages of the
reaction (Fig. 3C
). Finally, experiments performed with
mouse instead of human cell extract as a source of repair factors
revealed identical excision preferences. In fact, the mouse nucleotide
excision repair enzymes were able to remove
B[a]P-N6-dA adducts
located in the N-ras codon 61 sequence but, as observed with
the human system, there was marginal or no repair of the corresponding
B[c]Ph adducts (gels not shown).
Comparison between B[a]P-DNA Adducts Targeted to
Different Sequence Environments.
Effective excision of
B[a]P-N6-dA adducts was
not limited to the N-ras codon 61 sequence context
5'-ACA*AG-3' (the asterisk denotes the modified
adenosine). A similar level of excision was observed when the same (+)-
and
(-)-trans-anti-B[a]P-N6-dA
adducts were located in the unrelated sequences 5'-TCA*CG-3' (Fig. 4
, Lanes 5 and 6) or 5'-TCA*CT-3' (data not
shown). Interestingly, all these (+)- and
(-)-trans-anti-B[a]P-N6-dA
adducts were processed nearly as efficiently as a series of single
(+)-trans-anti-B[a]P adducts
covalently linked to position N2 of
guanine in the sequence 5'-CGGGA-3' (Fig. 4
, Lanes 1–3),
which, because of its run of contiguous guanines, often represents a
hot spot for B[a]P-induced mutagenesis (46)
.
Thus, we observed excision of
B[a]P-N6-dA or
B[a]P-N2-dG adducts
regardless of the particular nucleotide sequence environment;
therefore, the ability to remove these adducts (although with variable
efficiency) seems to be a general property of the human nucleotide
excision repair system.
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, Lanes 1 and 2). The specific
excision products are evidenced in the longer autoradiographic exposure
shown in Fig. 5B
(Lanes 1 and 2). A
direct comparison between Lanes 1 and 7 (Fig. 5B
) suggests that the
(+)-trans-anti-B[a]P-N6-dA
adduct is excised more efficiently from the N-ras than from
the H-ras sequence. Interestingly, we also found comparable
levels of oligonucleotide excision when the configuration of these
B[a]P-N6-dA adducts was
changed from anti to syn (Fig. 5, A and B
, Lanes 3 and 4). However,
excision repair of adenine lesions in the identical sequence context
was abolished when the bay region B[a]P adduct was
replaced by the fjord region B[c]Ph residue. In fact, (+)-
and
(-)-trans-anti-B[c]Ph-N6-dA
adducts located at the same second position of H-ras codon
61 were unable to stimulate any observable excision of the modified
sequences (Fig. 5, A and B
, Lanes 5
and 6). Laser scanning densitometry of
24–32-nucleotide-long excision products from three different assays,
each performed with independent substrate and cell extract
preparations, support our conclusion that the tested
B[c]Ph-N6-dA adducts are
resistant to removal by human excision repair enzymes (Fig. 5C
).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Using a standard assay in cell extracts, we found
that human nucleotide excision repair enzymes process a broad range of
bay region B[a]P lesions, including the (+)- or
(-)-trans-anti-B[a]P-dA adducts
that are formed relatively inefficiently when B[a]P
diol-epoxides react with native DNA (29)
. However, we
observed that the same excision repair system fails to remove the major
fjord region (+)- or
(-)-trans-anti-B[c]Ph-N6-dA
adducts resulting from the reaction of (+)- or
(-)-anti-B[c]Ph diol-epoxide with DNA. This
lack of B[c]Ph excision was established using the codon
60–62 context of both human N-ras (GGACA*AGAA) and
H-ras (GGCCA*GGAG) proto-oncogene sequences, in which the
asterisks denote the covalently modified adenosine at the
second position of codon 61. The differential repair activity in response to B[a]P- and B[c]Ph-N6-dA adducts is related to the distinct conformational properties that these lesions impose on the DNA double helix. For example, nuclear magnetic resonance analysis showed that the bay region (-)-trans-anti-B[a]P-N6-dA adduct is inserted into the Watson-Crick double helix, thereby inducing a modest but detectable distortion of base pairing interactions at the site of covalent modification (47) . In contrast, the corresponding fjord region (+)- and (-)-trans-anti-B[c]Ph-N6-dA adducts are incorporated into the double helix by an intercalative mode that retains normal Watson-Crick base pairing throughout the modified duplexes (48 , 49) . These nuclear magnetic resonance models are supported by differences in the thermodynamic stability of short double-stranded fragments containing a single bay region or fjord region polycyclic aromatic hydrocarbon adduct. In fact, the DNA duplex melting point is significantly lowered by (+)- or (-)-trans-anti-B[a]P-N6-dA lesions (50) , indicating a weakening of Watson-Crick hydrogen bonds, whereas the melting point is unchanged in the presence of the corresponding B[c]Ph-N6-dA lesions (32) . On the basis of these biophysical studies, the poor repairability of B[c]Ph-N6-dA lesions confirms recent reports from one of our laboratories in which the use of artificial DNA substrates led to the conclusion that destabilization of local base pairing constitutes an essential molecular signal for recruitment of the human nucleotide excision repair system (38 , 51) . We also found that this specific conformational requirement for nucleotide excision is mediated by the extraordinary affinity of the xeroderma pigmentosum group A protein-replication protein A complex for sites of defective base pairing (51) . Thus, nondistorting carcinogen-DNA adducts that maintain normal Watson-Crick base pairing, such as, for example, (+)- or (-)-trans-anti-B[c]Ph-N6-dA, fail to attract the initial recognition subunits of the excision repair system and, as a consequence, remain unrepaired. Interestingly, we found that poor repairability is not limited to the B[c]Ph-N6-dA lesions. In fact, similar experiments in HeLa cell extract showed that at least four other representatives with the fjord structural motif, i.e., (+)- and (-)-trans-anti-benzo[g]chrysene-N6-dA (containing the same number of aromatic ring systems as B[a]P) or (+)- and (-)-trans-anti-dibenzo[a,l]pyrene-N6-dA (containing an additional aromatic ring compared to B[a]P) are equally unable to induce excision repair reactions.4 Taken together, these findings raise the possibility that stable adenine adducts of fjord region polycyclic aromatic hydrocarbons might be generally incompatible with recognition by the human nucleotide excision repair system.
In summary, our report reveals that the exceptional tumorigenic activity of B[c]Ph diol-epoxides or other similar fjord region metabolites correlates with the formation of deoxyadenosine adducts that, at least in some crucial target sequences such as H-ras or N-ras codon 61, are resistant to removal by DNA repair enzymes. These results are consistent with the expectation that inefficient excision constitutes an important determinant of tumorigenic potency. As a consequence, even minor polycyclic aromatic hydrocarbon lesions that are formed with only low efficiency may exert disproportionately large genotoxic effects because of extremely slow repair. This report supports the notion that improved risk assessment procedures, particularly in the problematic low-dose range, require a more complete knowledge of the efficiency with which relevant carcinogen adducts are removed from critical mutational hot spots. Future experiments will be devoted to testing whether excision from short DNA fragments in cell extract accurately represents how the nucleotide excision repair system recognizes carcinogen-DNA adducts formed in oncogene or tumor suppressor gene sequences in intact cells.
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FOOTNOTES |
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1 Supported by Swiss National Science Foundation
Grant 3100-050518.97 (to H. N.), NIH/National Cancer Institute Grants
CA 20851 (to N. E. G) and 17613 (to S. A.), and Deutsche
Forschungsgemeinschaft Grant SFB 302 (to A. S.). 
2 To whom requests for reprints should be
addressed, at Institute of Pharmacology and Toxicology, University of
Zürich-Tierspital, August Forel-Strasse 1, CH-8008 Zürich,
Switzerland. Phone: 41-1-635-87-63; Fax: 41-1-635-89-10; E-mail: naegelih{at}vetpharm.unizh.ch
3 The abbreviations used are:
B[a]P, benzo[a]pyrene;
B[c]Ph, benzo[c]phenanthrene; HPLC,
high-performance liquid chromatography.
4 T. Buterin, H. Naegeli, N. Luneva, and N. E. Geacintov, unpublished results.
Received 9/24/99. Accepted 2/ 3/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. Proc. Natl. Acad. Sci. USA, 11: 5358-5361, 1978.
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