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Molecular Biology and Genetics |
Laboratory of Genetic Instability and Cancer, UPR 2169 CNRS, 94801 Villejuif Cedex, France [F. L. P., A. S.], and Laboratoire de Vectorologie et Transfert de gènes, CNRS UMR #1582 [V. R., D. M., J. C., M. P.] and Laboratoire de Génétique Oncologique, CNRS UMR #1599 [J. F.], Institut Gustave-Roussy, 94805 Villejuif Cedex, France
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Basic metabolic pathways produce reactive oxygen species that are potentially mutagenic, and the mammary tissue is particularly exposed to such oxidative stress because of specific hormone metabolism (9 , 10) . It is likely that the lack of an efficient oxidative lesion repair represents a significant contribution to breast cancer. 8-oxoG,4 one of the most damaging lesion among the numerous oxidized bases (11) , is produced in relatively high quantity and carries a high mutagenic potency because of the formation of a stable bp with adenine (12 , 13) . We have observed recently that 8-oxoG lesions located on a transcribed strand is repaired in a transcription-coupled fashion requiring the presence of CSB, XPG and TFIIH factors, whereas on the nontranscribed strand, it is repaired by the OGG1 glycosylase (14 , 15) . Therefore, base lesions induced by ionizing radiation (such as 8-oxoG or thymine glycols) on the transcribed strand, if not repaired, will lead to either transcription blockage and/or mutagenic bypass.
Altogether these observations have led us to postulate that BRCA1 or BRCA2 may participate in repair of the highly prevalent 8-oxoG lesion and that breast cancer cells in which either of the two genes is inactivated may be defective in this pathway. We have explored this possibility with a shuttle vector assay specifically designed to measure the level of repair of 8-oxoG lesions present on either a transcribed or a nontranscribed strand of the shuttle vector in human cells.
We show that human cancer cells deficient for BRCA1 or BRCA2 are impaired in the TCR of 8-oxoG. Expression of wild-type BRCA1 from a recombinant adenovirus fully complements the repair defect in BRCA1-deficient cells.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Plasmids.
PS189-
SVori has been described previously (18)
. The
vector deleted from its SV40 promoter region,
pS189-PSV, was obtained by deletion of the
HaeIII-BamHI fragment. Monomodified
plasmids based on pS189-SVori or pS189-PSV
were constructed using a [
-32P]ATP-modified,
19-mer oligonucleotide carrying a unique 8-oxoG in the sequence
GATCGGCGCCGGOCGGTGTG (corresponding to codons 10–14 of the
human Ha-ras gene), where the restriction site NgoMIV is
underlined, as already published (14
, 18)
. This sequence,
located 3' of the SV40 TAg gene and upstream of a polyadenylation
signal, can be transcribed or not, depending on the vector used (Fig. 1A)
.
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lac-pro F'pro lacI
lacZ, mutY::kan, fpg::kan, Tn10) with a Sedd Cell
Ject Apparatus (Bio-Rad, Ivry, France) <40 µF, 192 ohms, and 2500 V
(18)
. After plasmid DNA purification from individual
colonies (Promega Corp., Charbonnières, France), digestion by
NgoMIV, which cleaves only when the G:C bp is present at the site of
8-oxoG, is carried out. Nonmutated plasmid DNA was cut by NgoMIV
digestion. All uncut DNA correspond to mutants; 95% of them present a
G to T transversion targeted at the site of the original 8-oxoG
(18)
. The repair frequency was determined as the ratio
between NgoMIV-sensitive plasmids to total progeny plasmids normalized
to the frequency of vectors sensitive to NgoMIV digestion after direct
transfection in bacteria (without passage through human cells) of the
pS189-SVori/GO:C.
Transcription Analysis of the 8-oxoG-carrying Template.
Twelve h after transfection with the pS189-SVori/GO:C, transcripts
spanning either the coding sequence of the SV40 TAg (300 bp) or the
sequence around the 8-oxoG (270 bp), were amplified by RT-PCR analysis
performed on total RNA. The primers used for multiplex PCR analysis
permit the detection of transcripts from a 300-bp fragment hybridizing
inside the SV40 TAg gene and from a 270-bp fragment spanning the 8-oxoG
lesion (Fig. 1A)
. The primers used for the two
amplifications are, respectively: 5'-GAGCTTTAAATCTCTGTAGG-3' and
5'-TTATACGAGTAGTTGGACTG-3' for the 300 bp; and
5'-CTTGAGCGTCGATTTTTGTG-3' and 5'-GAACGAAATTTTTTGGAGGG-3' for the
270-bp fragment.
Expression of Wild-Type BRCA1 in Recombinant AdRSVBRCA1-infected
Cells.
AdRSVBRCA1 is an E1/E3-defective and nonreplicative recombinant
adenovirus of the Ad5 serotype. A full-length cDNA fragment encoding
the 1863 amino acids of human wild-type BRCA1 was subcloned between the
SalI and EcoRV sites of pAdRSVßgal plasmid
behind the long terminal repeat of the RSV to generate the pAdRSVBRCA1
adenoviral shuttle plasmid. AdRSVBRCA1 was constructed in 293 cells by
homologous recombination between pAdRSVBRCA1 recombinant shuttle vector
and ClaIrestricted AdRSVßgal viral DNA, amplified,
and purified as described previously (20)
. Viral
infections of HCC 1937 cells were performed with AdRSVßgal (control)
or AdRSVBRCA1 for 4 h at a multiplicity of infection of 200
(determined as the best compromise between efficiency of infection and
cytopathic effect). Whole-cell lysates were prepared at day 1 (D1) and
day 2 (D2) after infection. Fifty µg of total protein extracts were
separated on 6% SDS-PAGE, transferred on nitrocellulose filter, and
immunoblotted with an anti-BRCA1 antibody (OP 92; Oncogene Research
Products, Cambridge MA) as described (21)
. The zero time
for the kinetics of 8-oxoG repair corresponds to the 24-h time after
infection by the recombinant adenovirus.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A, which shows that during the first 4 h, the kinetics
of 8-oxoG removal is about twice faster when it is located on a TS
versus a NTS sequence in both normal human fibroblasts and
in MCF-7 breast cancer cells. Within 12 h, the removal of the
8-oxoG located on the NTS is complete in all cell lines tested (Fig. 2B)
. When located on the TS, the 8-oxoG is completely
removed within 8 h in cell lines carrying wild-type
BRCA1 or BRCA2 alleles (SV40-transformed normal
fibroblast cell line MRC5SV1 and tumor breast cell line MCF7; Fig. 2C
). By contrast, the removal of the 8-oxoG is totally
impaired in BRCA1-mutated HCC 1937 cells and 
90%
deficient in BRCA2-mutated CAPAN-1 cells (Fig. 2C)
. It is tempting to propose that this very clear repair
deficiency is attributable to the lack of BRCA1 or BRCA2 function.
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. By contrast, in
BRCA1-mutated cells, no transcript of the sequence
containing the 8-oxoG lesion was found, although normal transcription
of the SV40 TAg gene occurred (Fig. 1B)
. This observation
implies that the transcription machinery is blocked by the 8-oxoG
itself or by protein complexes recognizing the lesion, and that the RNA
polymerase II complex cannot proceed through the lesion in the absence
of repair. For the BRCA2-mutated cells, the 270-bp band was
detected but at a level corresponding to <20% of control cells (Fig. 1B)
. This result agrees with the low level of 8-oxoG repair
in this cell line (Fig. 2C)
.
Wild-Type BRCA1 Gene Product Rescues the Deficiency in Repair of
8-oxoG Lesion in HCC 1937 Cells.
A biologically active wild-type BRCA1 protein was restored in HCC 1937
cells by infection with a recombinant adenovirus. High-titer adenovirus
stocks give high yields of infection, allowing the study of a large
cell population expressing BRCA1. Infection of HCC 1937 cells by the
adenovirus expressing the ß-galactosidase gene
leads to gene transfer and expression in 80% of the infected cells
(data not shown). Cells infected by the recombinant adenovirus
(AdRSVBRCA1) express stable wild-type BRCA1 protein for at least
48 h (Fig. 3)
. Twenty-four h after infection of HCC 1937 cells by the AdRSVBRCA1
virus, the shuttle vector containing the 8-oxoG lesion was transfected.
The kinetics of repair of the lesion over the subsequent 12 h
shows a complete recovery of the 8-oxoG repair (Fig. 2D)
,
suggesting that in these cells, the repair defect can be fully
complemented by the restoration of BRCA1-associated functions. The
infection by an adenovirus vector, which expresses the bacterial
ß-galactosidase gene (AdRSVßGal), does not
complement the repair deficiency (Fig. 2D)
.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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HCC 1937 cells are unizygous for a mutant allele of the p53
gene (16)
. The lack of 8-oxoG repair in these cells is
unlikely to be linked to the absence of a functional p53 protein
because expression of BRCA1 is sufficient to fully restore the repair
to the wild-type level. Furthermore, SV40-transformed MRC5SV1 cells, in
which p53 is sequestered by the SV40 TAg, displays a normal repair
pattern (Fig. 2C)
.
TCR has been described essentially for UV-induced DNA lesions (23 , 24) because of the blockage of RNA polymerase II transcription. HCC 1937 cells exhibit normal survival after UVC (from 0 to 20 J/m2) and UVB (from 0 a to 500 J/m2) irradiation as well as normal unscheduled DNA synthesis.5 This result indicates that the BRCA1 protein is not directly involved in the TCR pathway specific for UV-induced DNA lesions and that the TCR pathway specific for 8-oxoG involves different components.
We already have demonstrated (14)
that the removal of
8-oxoG on TS is fully dependent on an active TCR process. This specific
removal is fully inhibited in CS cells as well as in cells from
patients exhibiting both CS and XP diseases (13)
. These
latter patients belong to XP group B, D, or G. This result indicates
that CSB, XPG, XPB, and XPD proteins are essential in the process of
8-oxoG TCR to prevent the blockage of RNA polymerase II by the 8-oxoG
or its removal from the template. As shown in Fig. 1
B, the
transcription machinery of BRCA1 and BRCA2 mutant cells is also blocked
by the 8-oxoG lesion. The effect of oxidative damage on transcription
has received little attention, particularly in mammalian cells. In
prokaryotes, in vitro studies led to conflicting
conclusions, because 8-oxoG lesions cause the termination transcription
by T7 polymerase (25)
but not by E. coli
polymerase (26)
. Nonetheless, the data presented here
demonstrate that in cells unable to repair 8-oxoG, RNA polymerase II is
unable to bypass the lesion, whereas it is able to do so in cells fully
proficient for 8-oxoG repair. The presence of stalled RNA polymerase
molecule at the lesion site in these defective cells provides a likely
explanation for the inability to remove it by the repair enzymes. It is
possible that binding of mismatch recognition proteins to 8-oxoG blocks
the progress of RNA polymerase and thus provides a signal for
preferential repair. Consistent with this scenario is the known
requirement for MSH2 in TCR of oxidative damage in both human cells and
yeast (27
, 28)
and the recognition of 8-oxoG:C and
8-oxoG:A mispairs by MSH2-MSH6 in Saccharomyces cerevisiae
(29)
. Using a two-hybrid assay, Bertrand et al.
(30)
reported that MSH2 exists in a complex with NER
proteins in S. cerevisiae. Recent data from our laboratory
showed slower removal of 8-oxoG in the transcribed strand of the
shuttle vector in human tumor cells lacking hMSH2 than in normal cells
but no difference in rate of removal between the two cell lines when
the 8-oxoG is in a
NTS.6
The existence of an 8-oxoG-specific DNA binding protein in human cells
was inferred from the inhibition of activity of purified hOGG1 on an
8-oxoG-containing oligonucleotide in vitro by addition of
whole-cell extract (31)
. Altogether these data provide a
rationale for a complex between mismatch repair proteins involved in
the blockage of RNA polymerase II. Recent data (32)
demonstrating interaction between BRCA1 and several DNA repair proteins
including mismatch repair partners support this hypothesis.
In this context, BRCA1 and BRCA2 proteins should intervene in synergy with the five repair proteins at steps yet unknown. The reported interactions between BRCA1 protein and RNA polymerase II, and the basal transcription factors TFIIF, TFIIE, and TFIIH (33 , 34) may imply protein-protein interactions at the site of RNA polymerase blockage. It is worthwhile recalling that the XPD and XPB helicases are present in the TFIIH complex (35) , leading to the hypothesis of a physical interaction between BRCA1, BRCA2, XPD, and XPB as part of the regulation of the TCR process specific for oxidative lesions. The putative interactions between CSB, CSA, and XPG proteins have not been established yet.
The understanding of breast oncogenesis in the context of BRCA1 or BRCA2 deficiency should now incorporate the observation that these proteins play a role in the repair of 8-oxoG and probably other oxidative lesions but not in classical NER such as UV-induced DNA lesion repair. Radical oxygen species, and particularly the hydroxyl radical OH·, or ionizing radiation can indeed oxidize DNA bases, giving rise to 8-oxoG, 8-oxo-adenine, Fapy derivatives, and thymine glycols (11) . Among these lesions, the 8-oxoG is probably the most abundant and mutagenic damage. A significant high level of these oxidized bases has been reported in several cancer tissues and particularly in breast carcinoma (9 , 36) . The origin of this high oxidation status of cancer cells is still not known but may be linked to the normal metabolism of estrogens. For example, a futile metabolism of 17ß-estradiol has been shown to produce hydrogen peroxide and probably singlet oxygen (10) . The relation between the oxidation metabolism of estrogens and breast cancer has been related in some epidemiological studies, where a given cytochrome P4501A1 gene polymorphism was associated with increased susceptibility to estrogen-related breast cancer in the African-American population (37) . Outside the induction of oxidized bases in DNA, the oxidative stress in breast cells can modulate the estrogen receptor functions and therefore participate in some type of tumor promotion (38) .
In conclusion, several studies reported a high level of oxidative stress in breast tissue that may be linked to estrogen metabolism and hormonal status. This state can produce oxidized DNA lesions such as the 8-oxoG. In the absence of a full error-free repair of this damage, mutations will occur at a very high frequency. We already observed that in cells from Cockayne’s patients unable to repair 8-oxoG, this unique residue gives rise to 30–40% mutations (14) , which confirms a high tendency of replication enzymes to pair this lesion with adenine (12) . We can therefore hypothesize that a breast cell already mutated on the BRCA1 or BRCA2 gene will be more susceptible to accumulate point mutations at a high frequency eventually on proto-oncogenes or tumor suppressor genes, leading to malignancy. The BRCA1 and BRCA2 mutations, carried by the HCC 1937 and the CAPAN-1 cells, respectively, are among the most prevalent mutations linked to familial breast and ovarian cancers (39) . The deficiency in the repair of 8-oxoG linked to the genetic status reported here thus represents a model highly relevant to the hereditary predisposition to breast and ovarian cancers.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by a Contrat Libre (No.
9023) from Association pour la Recherche sur le Cancer (ARC), a
grant from the "Ministère de la Recherche et la Technologie"
(ACC-SV8, Paris, France), a grant from La Ligue Contre le Cancer, and a
grant from the "Service de Radioprotection de l’EDF" (Paris). 
2 Present address: UMR217 CEA-CNRS, Laboratoire de
Radiobiologie du DNA, 92265 Fontenay-aux-Roses, France.
3 To whom requests for reprints should be
addressed, at Laboratory of Molecular Genetics, UPR 2169 Centre
National de la Recherche Scientifique, BP no. 8, 94801 Villejuif Cedex,
France. Phone: 33-1-49-58-34-20; Fax: 33-1-49-58-34-11; E-mail: sarasin{at}infobiogen.fr
4 The abbreviations used are: 8-oxoG or GO,
8-oxoguanine; RT-PCR, reverse transcription-PCR; RSV, Rous sarcoma
virus; TS, transcribed sequence; NTS, nontranscribed sequence; TCR,
transcription-coupled repair; NER, nucleotide excision repair; TAg, T
antigen; CS, Cockayne’s syndrome; XP, xeroderma pigmentosum; ßgal,
ß-galactosidase.
5 A. Sarasin, unpublished observation.
6 F. Le Page and A. Sarasin, unpublished
data.
Received 12/16/99. Accepted 8/ 2/00.
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REFERENCES |
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, TS; 
, NTS. HCC 1937: 
, TS; 
, NTS. HCC 1937 + ßgal:
, TS. HCC
1937 + BRCA1: 
, TS. CAPAN-1: 
, TS; 
, NTS. MRC5SV1:
,
TS,
,
NTS.