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BRCA1 and BRCA2 Are Necessary for the Transcription-Coupled Repair of the Oxidative 8-Oxoguanine Lesion in Human Cells1

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BRCA1 and BRCA2 Are Necessary for the Transcription-Coupled Repair of the Oxidative 8-Oxoguanine Lesion in Human Cells1 [CANCER RESEARCH 60, 5548–5552, October 1, 2000] BRCA1 and BRCA2 Are Necessary for the Transcription-Coupled Repair of the Oxidative 8-Oxoguanine Lesion in Human Cells1 Florence Le Page,2 Voahangy Randrianarison, Didier Marot, Jeannine Cabannes, Michel Perricaudet, Jean Feunteun, and Alain Sarasin3 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 ge`nes, CNRS UMR #1582 [V. R., D. M., J. C., M. P.] and Laboratoire de Ge´ne´tique Oncologique, CNRS UMR #1599 [J. F.], Institut Gustave-Roussy, 94805 Villejuif Cedex, France ABSTRACT tity and carries a high mutagenic potency because of the formation of a stable bp with adenine (12, 13). We have observed recently The breast and ovarian cancer susceptibility genes, BRCA1 and that 8-oxoG lesions located on a transcribed strand is repaired in a BRCA2, are likely to participate in DNA lesion processing. Oxidative transcription-coupled fashion requiring the presence of CSB, XPG lesions, such as 8-oxoguanine, occur in DNA after endogenous or exoge- nous oxidative stress. We show that deficiency for either BRCA1 or and TFIIH factors, whereas on the nontranscribed strand, it is BRCA2 in human cancer cells leads to a block of the RNA polymerase II repaired by the OGG1 glycosylase (14, 15). Therefore, base lesions transcription machinery at the 8-oxoguanine site and impairs the tran- induced by ionizing radiation (such as 8-oxoG or thymine glycols) scription-coupled repair of the lesion, leading to a high mutation rate. on the transcribed strand, if not repaired, will lead to either Expression of wild-type BRCA1 from a recombinant adenovirus fully transcription blockage and/or mutagenic bypass. complements the repair defect in BRCA1-deficient cells. These results Altogether these observations have led us to postulate that BRCA1 represent the first demonstration of the essential contribution of BRCA1 or BRCA2 may participate in repair of the highly prevalent 8-oxoG and BRCA2 gene products in the repair of the 8-oxoguanine oxidative lesion and that breast cancer cells in which either of the two genes is damage specifically located on the transcribed strand in human cells. This inactivated may be defective in this pathway. We have explored this suggests that cells from individuals predisposed to breast and/or ovarian possibility with a shuttle vector assay specifically designed to measure cancer may undergo a high rate of mutations because of the deficiency of this damage repair pathway after oxidative stress. 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 INTRODUCTION are impaired in the TCR of 8-oxoG. Expression of wild-type BRCA1 from a recombinant adenovirus fully complements the repair defect in Germ-line mutations in either the BRCA1 or the BRCA2 gene are BRCA1-deficient cells. responsible for the majority of hereditary breast cancers (1). Although the precise biological activities of these two genes are still unknown, it is now widely accepted that they belong to a group of molecules that MATERIALS AND METHODS participate in the monitoring and/or the repair of DNA lesions (2, 3). The relaxation of this monitoring caused by mutations of either of Cells. MRC5SV1 is a normal human fibroblast cell line transformed by these two genes leaves unrepaired events that lead to the accumulation SV40. MCF7 is a breast tumor-derived cell line (BRCA1ϩ/ϩ, BRCA2ϩ/ϩ, ϩ ϩ of mutations and ultimately to cancer. BRCA1 appears to play a role and p53 / ). HCC 1937 is a cell line derived from a breast tumor in a woman carrying a 5382 insC germ-line mutation of BRCA1. The tumor cells have in two unrelated repair processes. On the one hand, the capacity of the retained the mutant allele and lost the wild-type allele. It also carries a BRCA1 protein to interact with hRAD51 and to promote homologous unizygous mutation of p53 (R306Stop) and a deletion of the PTEN gene (16). recombination are strong indications for a role in recombination repair CAPAN-1 cells are derived from a pancreatic carcinoma from an individual (4, 5). On the other hand, human BRCA1 and murine brca1 may presumably carrying a germ-line mutation in BRCA2 (6174delT). The cell line participate in transcription-coupled DNA repair of some ionizing is unizygous for this mutation (17). radiation-induced DNA lesions (6, 7). The role of murine brca2 in Plasmids. PS189-⌬SVori has been described previously (18). The vector ⌬ DNA repair is also well documented (8). deleted from its SV40 promoter region, pS189- PSV, was obtained by deletion Basic metabolic pathways produce reactive oxygen species that of the HaeIII-BamHI fragment. Monomodified plasmids based on pS189- ⌬ ⌬ ␥ 32 are potentially mutagenic, and the mammary tissue is particularly SVori or pS189- PSV were constructed using a [ - P]ATP-modified, exposed to such oxidative stress because of specific hormone 19-mer oligonucleotide carrying a unique 8-oxoG in the sequence GATCG- GCGCCGGOCGGTGTG (corresponding to codons 10–14 of the human Ha- metabolism (9, 10). It is likely that the lack of an efficient oxida- ras gene), where the restriction site NgoMIV is underlined, as already pub- tive lesion repair represents a significant contribution to breast Ј 4 lished (14, 18). This sequence, located 3 of the SV40 TAg gene and upstream cancer. 8-oxoG, one of the most damaging lesion among the of a polyadenylation signal, can be transcribed or not, depending on the vector numerous oxidized bases (11), is produced in relatively high quan- used (Fig. 1A). Repair Assay. Repair analysis was performed following a similar experi- Received 12/16/99; accepted 8/2/00. mental protocol as described previously (14). Transfections of nonreplicating The costs of publication of this article were defrayed in part by the payment of page monomodified plasmids into the different cell lines were mediated using the charges. This article must therefore be hereby marked advertisement in accordance with FuGene procedure (Roche, Meylan, France). Cells were incubated for the 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by a Contrat Libre (No. 9023) from Association pour la indicated times and collected. Efficient elimination of any contaminating DNA Recherche sur le Cancer (ARC), a grant from the “Ministe`re de la Recherche et la input before extracting plasmid DNA from cells was performed by treatment Technologie” (ACC-SV8, Paris, France), a grant from La Ligue Contre le Cancer, and a of cell cultures with Dnase I. Extrachromosomal plasmid DNA was recovered grant from the “Service de Radioprotection de l’EDF” (Paris). 2 by a small-scale alkaline lysis method (19) and used to transform by electro- Present address: UMR217 CEA-CNRS, Laboratoire de Radiobiologie du DNA, ␮ Ϫ Ϫ 92265 Fontenay-aux-Roses, France. poration 40 lofEscherichia coli PR195 fpg /mutY double mutant bacteria 3 To whom requests for reprints should be addressed, at Laboratory of Molecular unable to remove 8-oxoG (⌬lac-pro FЈpro lacI lacZ, mutY::kan, fpg::kan, Genetics, UPR 2169 Centre National de la Recherche Scientifique, BP no. 8, 94801 Tn10) with a Sedd Cell Ject Apparatus (Bio-Rad, Ivry, France) Ͻ40 ␮F, 192 VillejuifCedex,France.Phone:33-1-49-58-34-20;Fax:33-1-49-58-34-11;E-mail:sarasin@ infobiogen.fr. 4 The abbreviations used are: 8-oxoG or GO, 8-oxoguanine; RT-PCR, reverse tran- sequence; TCR, transcription-coupled repair; NER, nucleotide excision repair; TAg, T scription-PCR; RSV, Rous sarcoma virus; TS, transcribed sequence; NTS, nontranscribed antigen; CS, Cockayne’s syndrome; XP, xeroderma pigmentosum; ␤gal, ␤-galactosidase. 5548 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2000 American Association for Cancer Research. BRCA1 AND BRCA2 IN THE REPAIR OF 8-OXOGUANINE LESION the ratio between NgoMIV-sensitive plasmids to total progeny plasmids nor- malized 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: 5Ј-GAGCTTTAAATCTCTG- TAGG-3Ј and 5Ј-TTATACGAGTAGTTGGACTG-3Ј for the 300 bp; and 5Ј-CTTGAGCGTCGATTTTTGTG-3Ј and 5Ј-GAACGAAATTTTTTGGAG- GG-3Ј for the 270-bp fragment. Expression of Wild-Type BRCA1 in Recombinant AdRSVBRCA1- infected Cells. AdRSVBRCA1 is an E1/E3-defective and nonreplicative re- combinant 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 pAdRSV␤gal plasmid behind the long terminal repeat of the RSV to generate the pAdRSVBRCA1 adenoviral shuttle plasmid. AdRSVBRCA1 was constructed in 293 cells by homologous recom- bination between pAdRSVBRCA1 recombinant shuttle vector and ClaI- restricted AdRSV␤gal viral DNA, amplified, and purified as described previ- ously (20). Viral infections of HCC 1937 cells were performed with AdRSV␤gal (control) or AdRSVBRCA1 for4hatamultiplicity 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.
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