From the Section of Molecular Signaling and
Oncogenesis, Division of Clinical Sciences, NCI, National
Institutes of Health, Bethesda, Maryland, 20892 and the
§ Curriculum in Genetics and Molecular Biology and the
Lineberger Comprehensive Cancer Center, University of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599
Received for publication, May 22, 2001
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ABSTRACT |
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BRCA1 gene is a tumor suppressor for
breast and ovarian cancers with the putative role in DNA repair and
transcription. To characterize the role of BRCA1 in transcriptional
regulation, we analyzed gene expression profiles of mouse embryonic
stem cells deficient in BRCA1 using microarray technology. We
found that loss of BRCA1 correlated with decreased expression of
several groups of genes including stress response genes, cytoskeleton genes, and genes involved in protein synthesis and degradation. Previous study showed that BRCA1 is a transcriptional co-activator of
p53 protein; however the majority of p53 target genes remained at the
same expression levels in BRCA1 knockout cells as in the wild type
cells. The only p53 target gene down-regulated with the loss of BRCA1
was 14-3-3 Mutations in BRCA1 gene are linked to inherited breast and ovarian
cancers. The biological function of BRCA1 is not clearly understood.
Primary cells deficient in BRCA1 have decreased growth rate, altered
chromosome stability, and G2/M checkpoint control (1-5).
Evidence suggests that BRCA1 is involved in a number of DNA repair
pathways, with BRCA Another putative function of BRCA1 is in the regulation of
transcription. BRCA1 interacts with a number of transcription factors or modifiers of transcription like p53, c-Myc, CtIP·CtBP,
STAT1, and p300 (14-19). Binding to different transcription factors
results in a diverse biological outcome. For example, BRCA1 induces the transcription of cell cycle regulators cyclin-dependent
kinase inhibitor p21 and GADD45 by virtue of p53 transcriptional
co-activation or represses the expression of the same genes when
silencing ZBRK1 transcription factor through the CtIP·CtBP complex
(20). Mutations identified in the C terminus of BRCA1 from breast
cancer patients were unable to activate transcription, inferring the
importance of transcriptional activating function for BRCA1 tumor
suppression activity.
To characterize the role of BRCA1 in transcriptional regulation, we
analyzed gene expression profiles of ES cells with targeted deletion of
full-length BRCA1 gene. We found that loss of BRCA1 results in
decreased expression of stress response genes, cytoskeletal genes, and
14-3-3 Expression and Reporter Plasmids--
The 14-3-3 Cell Cultures--
Generation of ES cells with the targeted
deletion of exon 11 of the BRCA1 gene and BRCA1-deficient ES cells
transfected with a BRCA1 transgene were described in Refs. 1 and 8.
Mcf7 breast carcinoma, HCT116, RKO, SW480, and HT29 colon cancer
cell lines were purchased from American Type Culture Collection and cultured in recommended growth media. HCC1937 cells were a gift from Dr. Mel Campbell and Dr. Roy Jensen (Vanderbilt University, Nashville, TN). Cells were irradiated using a 137Cs
Microarray Analysis--
Messenger RNA was isolated from ES
cells using a FastTrack 2.0 kit (Invitrogen, Carlsbad, CA). 2 µg of
mRNA was reverse transcribed using T7(dT)24 primer and
then labeled with biotinylated ribonucleotides incorporated by T7 RNA
polymerase. Resultant RNA was fragmented and hybridized to an
oligonucleotide microarray Mu6500 chip (Affymetrix, Santa Clara, CA)
according to the manufacturer's recommendations. BRCA1 Northern Blot Analysis--
Total RNA was isolated using Trizol
Reagent (Life Technologies, Inc.), and 20 µg was used for analysis. A
probe containing the 3'-untranslated region of the mouse 14-3-3 Flow Cytometry--
ES cells were Infection with Adenoviruses--
The amount of virus for
infection was variable (50 multiplicity of infection/cell for HCT116 or
500 multiplicity of infection/cell for Mcf7 and RKO) to provide about
two times overexpression of BRCA1. 16 h after infection total RNA
was analyzed for 14-3-3 Luciferase Reporter Assay--
Cells were split 24 h prior
to the experiment into 60-mm plates and transfected at about 60%
density with LipofectAMINE 2000 (Life Technologies, Inc.) according to
the manufacturer's instructions. Briefly, each transfection reaction
contained 0.5 µg of luciferase reporter and 0.2 µg of lacZ plasmid
as an internal standard. Where indicated cells were transfected with 1 µg of p53 expression vector (or mutant p53-273H) and 12 µg of
pcDNA3-BRCA1 (or pcDNA3-BRCA1 Differential Gene Expression in BRCA1-deficient Cells--
To
identify the impact of loss of BRCA1 function, we compared the gene
expression in the following three cell lines: wild type ES
cells, ES cells deficient in BRCA1 expression as a result of targeted
mutation of exon 11 (these cells will be termed
BRCA1
Of the 6,500 gene elements represented in the array, 51 genes were
expressed at more than two times higher levels in the presence of
either the wild type or the reconstituted BRCA1, whereas no genes were
down-regulated by BRCA1 within the stringent definition of outliers
(see Table I in Supplemental Material). Expression of several genes
involved in regulation of transcription was reduced with BRCA1
deletion. Included in this group is Id3, a dominant negative inhibitor
of transcription. Id3 gene is induced during early G1
phase, following by a second peak of induction in the late
G1 or early S phase coincident with the expression of
BRCA1. Partial inactivation of Id3 protein by antisense oligonucleotide or antibody microinjection results in a delayed entry of cells into the
S phase of cell cycle. Similar to BRCA1, overexpression of Id3 induces
apoptosis (22). Using Northern blot analysis we have confirmed that
both the wild type and BRCA1-tg ES cells express higher levels of Id3
gene than BRCA1
Loss of the BRCA1 resulted in reduced expression of a diverse group of
genes involved in cytoskeleton reorganization including multiple forms
of Down-regulation of 14-3-3 BRCA1
In the previous study, p53 was identified as a transcriptional factor
responsible for 14-3-3 Induction of 14-3-3
The ability of BRCA1 to modify 14-3-3 The focus of this work is to characterize the changes in the gene
expression in cells with targeted deletion of BRCA1 exon 11. Of the
list of 51 genes induced by BRCA1, we focused on 14-3-3 Previous microarray analysis of gene expression in the U2OS
osteosarcoma cell line after induction of the BRCA1 protein did not
show 14-3-3 Our results show that the expression of the 14-3-3, a major G2/M checkpoint control gene.
Similar to cells with decreased 14-3-3
activity, BRCA1-deficient cells were unable to sustain G2/M growth arrest after
exposure to ionizing radiation. We find that BRCA1 induction of
14-3-3
requires the presence of wild type p53 and can be regulated
by a minimal p53 response element.
INTRODUCTION
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
/
embryonic stem
(ES)1 cells being impaired in
their ability to perform homologous recombination and
transcription-coupled repair after oxidative DNA damage (6-8). After
DNA damage BRCA1 protein is phosphorylated and activated by ATM, ATR,
and Chk2 protein kinases, major regulators of DNA damage response
(9-11). This phosphorylation initiates relocation of the BRCA1 protein
inside the nuclei to the sites of DNA repair and most likely ensures
its interaction with other proteins implicated in homologous
recombination and double-strand break repair (12, 13).
, a major G2/M checkpoint control gene.
Irradiation of BRCA1-deficient cells showed the preliminary exit from
G2/M growth arrest similar to cells with targeted deletion
of 14-3-3
(21). BRCA1 protein overexpression activated the 14-3-3
promoter or induced transcription of the endogenous 14-3-3
in a
p53-dependent manner.
EXPERIMENTAL PROCEDURES
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
promoter
cloned upstream of luciferase gene was a gift of Dr. B. Vogelstein
(Johns Hopkins University) and is described in Ref. 28, and p53 wild
type, mutant p53-273H, and pG13-luc were obtained from
Dr. Kevin Gardner (NCI, NIH, Gaithersburg, MD). PcDNA3-BRCA1 wild
type was a gift of Dr. M. Erdos (NHGRI, NIH, Bethesda, MD).
PcDNA3-BRCA1
C has a deletion of 94 C-terminal amino acids.
PcDNA3.1/His/lacZ plasmid was purchased from Invitrogen (Carlsbad, CA).
-irradiator at total dosage of 10 Gy.
/
mRNA hybridization was repeated twice, and
data from each hybridization were used as a baseline for comparison
with BRCA1+/+ and BRCA1-tg cells. Comparison of gene
expression was performed with GeneChip analysis software. Signal
intensities for different chips were scaled to the target value of 150 for GAPDH gene (3' and M probes). The genes were excluded from the list
of outliers if the decision algorithm used negative values of average
differences. Only genes reproduced in 3 of 4 cross-comparisons
resulting in more than 2-fold difference were considered as true outliers.
gene
was generated by polymerase chain reaction using expressed
sequence tag AA873962 (Research Genetics, Huntsville, AL) and M13
forward and reverse primers. A 14-3-3
human probe was also generated
by polymerase chain reaction from the 3'-untranslated region as
described in Ref. 26. To generate mouse BRCA1 probe, an internal 4.5 kilobase pair EcoRI fragment was isolated.
Hybridizations were performed in QuickHyb solution using the
manufacturer's instructions (Stratagene).
-irradiated with a dose of
10 Gy and collected at the indicated time points. 106 cells
were fixed with 70% ethanol and stained with propidium iodide, and
amounts of DNA per cell were determined using FACScan (Becton Dickinson).
or BRCA1 expression by Northern blotting.
C). The total amount of DNA was
balanced with equimolar amount of empty vector. In 24 h cells were
washed with phosphate-buffered saline, scraped into 400 ml of 0.25 M Tris, pH 8.0, and snap frozen in dry ice. After two
rounds of freeze-thaw cellular lysates were cleared by centrifugation,
10 µl of lysate was tested for
-gal activity using a
-gal assay
kit (Invitrogen, Carlsbad, CA), and 5-10 µl of lysate was used to
measure luciferase activity (luciferase assay system, Promega, Madison, WI).
RESULTS
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
/
), and BRCA1
/
ES cells
reconstituted by transfection with a mouse BRCA1 cDNA expression
vector, transgene. Amplified mRNA from these cells was hybridized
to an oligonucleotide microarray (Mu6500; Affymetrix). We considered as
outliers the genes whose altered expression in BRCA1
/
cells compared with BRCA1+/+ cells was at least partially
restored after ectopic expression of a BRCA1 transgene in the
BRCA1
/
cells. Some BRCA1 regulated genes may not have
achieved outlier status in our list, because the level of BRCA1
transgene expression was lower than that in the wild type cells, and
therefore the reconstitution of BRCA1 expression was not complete (see
Fig. 1A and Ref. 7).
Nevertheless, this approach allowed us to increase the reliability of
the results increasing the probability that the expression of these
genes is directly or indirectly regulated by BRCA1.
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Fig. 1.
14-3-3 is
down-regulated in BRCA1
/
cells.
A, Northern blot analysis of 14-3-3
and BRCA1
gene expression in the parental embryonic stem cells (+/+),
cells deficient in BRCA1 (
/
), and
/
cells transfected with BRCA1 cDNA expression vector
(tg). B, induction of the 14-3-3
gene in ES
cells after irradiation. BRCA1+/+ and
/
cells were irradiated at 10 Gy, and the amount of 14-3-3
transcript
was analyzed by Northern blotting. Average data from three independent
experiments is presented. BRCA1+/+,
;
BRCA1
/
,
. C, cell cycle analysis of
BRCA1+/+, BRCA1
/
, or BRCA1-tg cells after
exposure to 10-Gy irradiation. Cells were collected at different time
points after irradiation and analyzed by flow cytometry. The amount of
cells in each phase of the cell cycle is presented in the right
panel. BRCA1+/+, solid line;
BRCA1
/
, thin line; BRCA1-tg, dotted
line.
/
cells (data not shown).
-actin, ROCK kinase, stabilizing stress fibers, cytokeratin, vimentin, and tropomyosin. Cell cycle progression is
associated with dramatic changes in the organization of cytoskeletal filaments. Expression of these genes is induced during
S-G2/M phase of cell cycle (23) and repressed during
oncogenic transformation. Similar to the study reported here,
microarray analysis of genes induced by p53 revealed up-regulation of
genes encoding cytoskeletal proteins (24). We also found decreased
expression of the Pw1 gene in BRCA1
/
cells. This gene
is activated during p53/c-Myc-mediated apoptosis but not during
p53-dependent G1 arrest, suggesting that Pw1
cooperates with p53 in determining the choice between cell death and
survival (25). A number of the genes with altered expression are
involved in protein synthesis and degradation, as well as heat shock
genes, whose products are known to modify protein folding in response to cellular stress.
Gene in
BRCA1
/
Cells--
We consistently found
decreased expression of 14-3-3
in the BRCA1-deficient cells.
Northern blot hybridization of RNA prepared from the three cell lines
confirmed the differences obtained on analysis of our microarray data
(Fig. 1A). In addition, this induction is specific for
14-3-3
in that other 14-3-3 family members did not change with the
BRCA1 status. Previous studies have shown that 14-3-3
gene is
induced after genotoxic stress (26). We, therefore, determined whether
expression of BRCA1 could modify the cellular response to
-irradiation using 14-3-3
expression as the read out. Our results
show that induction of 14-3-3
transcripts is significantly depressed
in BRCA1
/
ES cells after exposure to 10 Gy of
-irradiation (Fig. 1B).
/
Cells Exit G2/M Growth Arrest
Prematurely--
The 14-3-3
gene product is an important mediator
of G2/M checkpoint control, blocking progression of cells
with DNA damage through mitosis by retention of the CDC2·cyclin B
complex in the cytoplasm (21). Therefore, 14-3-3
/
cells arrest in G2/M phase of the cell cycle after exposure
to DNA-damaging agents but exit this arrest prematurely. We determined whether the loss of BRCA1 and consequent decreased expression of
14-3-3
leads to similar alteration of cell cycle regulation in ES
cells and whether these changes could be restored by expression of the
BRCA1 transgene. Wild type, BRCA1
/
, and BRCA1-tg cells
were irradiated, and cell cycle progression was measured over the next
24 h. ES cells do not display an arrest in G1. Thus,
after exposure to irradiation, the G1 population decreased
whereas the number of cells in G2 increased dramatically. After 4 h, all three ES cell lines had a similar arrest in
G2/M (Fig. 1C). However, even at 8 h
post-irradiation, the number of BRCA1
/
cells in
G2/M phase of cell cycle was significantly lower than that
in parental BRCA1+/+ or BRCA1-tg cells. Moreover, the
premature reentry of the BRCA1
/
cells into the cell
cycle was observed by the increase in the number of cells in
G1 at the later time points. This pattern of behavior
strikingly resembles that of 14-3-3
/
cells and
suggests a functional consequence of the attenuated 14-3-3
expression in the BRCA1-disrupted ES cells after DNA damage.
induction after DNA damage (26). Therefore,
we examined the status of p53 expression in BRCA1
/
cells. Neither microarray nor Northern blot analysis revealed any
difference in levels of p53 transcript between these cell lines.
Analysis of p53 protein by Western blot showed no differences in
protein level or in phosphorylation of serine in position 15 of p53 in
untreated wild type or BRCA1
/
cells (data not shown).
8 h after irradiation, phosphorylation of p53, as well as p21
protein, rose to similar levels in the parental and BRCA1-deficient
lines. These results show that the decreased expression of 14-3-3
in
BRCA1
/
cells is not associated with changes in the p53 protein.
by BRCA1 Overexpression in p53-positive
Human Cells--
To obviate the possibility that decreased expression
of 14-3-3
gene may be unique to mouse ES cells used in our
microarray experiments, we infected several human cancer cell lines
with adenovirus encoding the BRCA1 gene. The 14-3-3
transcript was induced in all three cancer cell lines, harboring wild type p53 genes
(Fig. 2A). Isogenic virus
encoding truncated BRCA1 protein was significantly less potent in
inducing 14-3-3
expression (Fig. 2B). When we used the
colon cancer cell line SW480, which is deficient in p53 protein, or the
breast carcinoma cell line HCC1937, which is deficient in both p53 and
BRCA1, no increase in 14-3-3
transcription was observed (Fig.
2C). Somasundaram et al. (27) reported that BRCA1
overexpression results in an increase in p53 protein levels 24 h
after infection with adenovirus, and this increase is dependent on
p14ARF. To verify that 14-3-3
induction after adenovirus-mediated BRCA1 overexpression was not a secondary reaction because of p53 protein stabilization we monitored the amount of 14-3-3
transcript and levels of p53 and BRCA1 proteins at various time points after infection. (Fig. 3A). The
BRCA1 protein was easily detectable 8 h after infection, and
induction of 14-3-3
transcripts expression was observed within the
first 12 h of the experiment. In contrast, p53 induction could not
be measured until at least 20 h post-infection. Together with
previous data this observation suggests that whereas p53 is required
for induction of 14-3-3
, BRCA1 can modulate expression of this
gene.
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Fig. 2.
Northern blot analysis of
14-3-3 induction by BRCA1 overexpression in
human cells. A, p53-positive mammary carcinoma cell
line Mcf7 or colon cancer cell lines HCT116 and RKO induced 14-3-3
gene expression after infection with adenovirus encoding BRCA1 compared
with empty virus (AE1). B, HCT116 cell line was
infected with adenovirus encoding wild type BRCA1 gene or mutated BRCA1
(1853-Stop) deficient in transcriptional activation.
C, p53-negative colon cancer cell line SW480 and BRCA1 and
p53 negative breast carcinoma cell line HCC1937 did not induce
14-3-3
after adenovirus-mediated BRCA1 overexpression.
Moi, multiplicity of infection.
View larger version (39K):
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Fig. 3.
BRCA1 cooperates with p53 in stimulation of
14-3-3 expression. A,
Northern blot analysis of 14-3-3
at different time after
adenovirus-mediated BRCA1 overexpression in HCT116 cell line.
GFP, green fluorescent protein. B, Western blot
analysis of p53 and BRCA1 protein at different time points after BRCA1
overexpression in HCT116 cell line. C, BRCA1 stimulates
p53-dependent transcription from the 14-3-3
promoter.
HT29 colon cancer cell line was co-transfected with the 14-3-3
reporter plasmid and pcDNA3-lacZ, as an internal standard, and
combinations of p53, mutant p53-273H and BRCA1, or
transactivation-deficient BRCA1 mutant. Cells were harvested 24 later,
and luciferase and
-gal activity were measured. D, as a
control, p53 artificial promoter pG13 (15) was used instead of the
14-3-3
promoter. Experiments were repeated at least three times in
duplicate. Representative experiments are shown.
expression was further tested
by examining transcription of a luciferase gene driven by the 14-3-3
promoter. This reporter plasmid was co-transfected with BRCA1 and/or
p53 expression vectors into two p53-negative colon cancer cell lines,
HT29 and SW480 (Fig. 3B and data not shown). As expected,
p53 gene alone induces luciferase gene expression. In contrast, BRCA1
alone had a very minor effect on the activity of the 14-3-3
promoter. However, when both p53 and BRCA1 were co-expressed,
transcription was induced to significantly higher levels than that
observed in cells transfected with p53 alone. The magnitude of
induction was comparable with that of an artificial promoter comprised
of 13 tandem p53 response elements (Fig. 3C). To further
verify the role of BRCA1 in increased activity of the 14-3-3
promoter, we compared the effectiveness of wild type and a mutant BRCA1
in this assay. We found that a C-terminal truncation mutant of the
BRCA1 was defective in its ability to co-activate transcription from
the 14-3-3
promoter. Our findings indicate that BRCA1 alone is a
very poor transcriptional activator of the 14-3-3
but that BRCA1 can
act synergistically to augment the ability of p53 to induce the
transcription of the 14-3-3
gene.
DISCUSSION
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
gene because
of its role in cell growth control. The importance of 14-3-3
protein
in mammary cell transformation is suggested by the fact that 14-3-3
expression is silenced in the majority of breast cancers (28). Previous
reports have suggested that BRCA1 is a transcriptional co-activator of
p53. However, we find that BRCA1 is not a broad co-activator but rather
a selective modulator of p53 transcription activity. The majority of
p53 target genes presented in the chip did not alter their transcript
levels with the loss of BRCA1. Obviously the most interesting question to address in the future will be to learn what other factors
influence the BRCA1 choice of transcriptional activation.
gene to be BRCA1 responsive (29). This may be explained
by cellular specificity of the 14-3-3
, which is expressed mainly in
epithelial cells. In agreement with this, we did not see induction of
14-3-3
in U2OS cells treated with adriamycin, unlike several
breast or colon cancer cell lines (data not shown). Another study of
downstream BRCA1 target genes focused mainly on p53-negative cells, and
the inability of BRCA1 to induce 14-3-3
gene expression confirms
that BRCA1 acts through p53 (30). Of note, both publications were
utilizing the overexpression of BRCA1 above the endogenous levels,
which may explain the differences in the set of genes activated by BRCA1.
checkpoint
control gene is modulated by the BRCA1 status of a cell. Moreover, optimal expression of 14-3-3
after DNA damage can be induced by a
synergistic effect between BRCA1 and p53. These data imply that
depending on the cellular context, BRCA1 can be a limiting factor in
maximal p53-dependent transactivation. Our findings might
also explain several clinical observations. First, there is increasing
information linking the loss of 14-3-3
expression to epithelial
transformation. Given the synergistic interaction between BRCA1 and p53
in regulating 14-3-3
expression described here, haploinsufficiency
in either BRCA1 or p53 genes might contribute to an inadequate
14-3-3
response to DNA damage and ultimately to transformation of
breast epithelium. Second, our observation suggests that mutation in
BRCA1 gene would compromise the 14-3-3
function, which is operative
mainly in epithelial cells. Thus, despite the ubiquitous expression of
BRCA1, its regulation of 14-3-3
expression might explain the
epithelial specificity of cancers in BRCA1 mutation carriers.
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ACKNOWLEDGEMENTS |
---|
We thank Dr. Vert Vogelstein for 14-3-3
reporter, Dr. Kevin Gardner for p53 and p53-273H expression vectors,
and Dr. Mel Campbell and Dr. Roy Jensen for adenoviruses.
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FOOTNOTES |
---|
* This work was supported in part by National Institutes of Health Grant CA82423 (to B. H. K.).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.
The on-line version of this article (available at
http://www.jbc.org) contains Table I.
¶ To whom correspondence should be addressed: ATC Bldg., Rm. 121, 8717 Grovemont Cr., Gaithersburg, MD 20878. Tel.: 301-435-5774; Fax: 301-402-3134; E-mail: apreliko@mail.nih.gov.
Published, JBC Papers in Press, May 30, 2001, DOI 10.1074/jbc.C100265200
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ABBREVIATIONS |
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The abbreviations used are: ES, embryonic stem; Gy, gray; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; tg, transgene.
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