Genomic Organization of Drosophila Poly(ADP-ribose)
Polymerase and Distribution of Its mRNA during Development*
Shuji
Hanai
,
Masahiro
Uchida
,
Satoru
Kobayashi§,
Masanao
Miwa
, and
Kazuhiko
Uchida
¶
From the
Department of Biochemistry and Molecular
Oncology, Institute of Basic Medical Sciences, and
§ Institute of Biological Sciences, Center for Tsukuba
Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki
305, Japan
 |
ABSTRACT |
Poly(ADP-ribosyl)ation of proteins catalyzed by
poly(ADP-ribose) polymerase (PARP; EC 2.4.2.30) modulates several
biological activities. However, little is known about the role of PARP
in developmental process. Here we report the organization of the Drosophila PARP gene and the expression patterns during
Drosophila development. The Drosophila PARP
gene was a single copy gene mapped at 81F and composed of six exons.
Organization of exons corresponds to the functional domains of PARP.
The DNA-binding domain was encoded by exons 1, 2, 3, and 4. The
auto-modification domain was encoded by exon 5, and the catalytic
domain was in exon 6. The promoter region of the PARP gene
contained putative TATA box and CCAAT box unlike human PARP. Expression
of the PARP gene was at high levels in embryos at 0-6 h
after egg laying and gradually decreased until 8 h. PARP mRNA
increased again at 8-12 h and was observed in pupae and adult flies
but not in larvae. In situ mRNA hybridization of
embryos revealed large amount of PARP mRNA observed homogeneously
except the pole cells at the early stage of embryos, possibly due to
presence of the maternal mRNA for PARP, and decreased gradually
until the stage 12 in which stage PARP mRNA localized in anal
plates. At late stage of embryogenesis PARP mRNA was localized in
cells along the central nervous system.
 |
INTRODUCTION |
Poly(ADP-ribose) polymerase (PARP; EC
2.4.2.30),1 a nuclear enzyme,
is activated by binding to a nick or end of double-stranded DNA and
catalyzes a sequential transfer reaction of ADP-ribose units from
-NAD+ to various nuclear proteins, forming a
protein-bound polymer of ADP-ribose units, poly(ADP-ribose) (for
reviews see, Refs. 1-4). Histones, topoisomerase, and PARP itself are
major acceptors in vivo. PARP cDNAs have been cloned
from phylogenetically distant species of eukaryotes like Xenopus
laevis (5, 6), cherry salmon (5), and Drosophila
melanogaster (7). PARP cDNA from Sarcophaga
peregrina (8) have also been reported. Two zinc fingers in the
DNA-binding domain and NAD-binding motifs in the catalytic domain were
conserved among different species (8, 9). Poly(ADP-ribosyl)ation of
proteins and turnover of poly(ADP-ribose) modulate biological processes
like DNA repair (10, 11), DNA amplification (12), cell cycle (13, 14),
transformation (15-17), carcinogenesis (18, 19), and cell death
(20-22). Thus, PARP has multifunctional features, but the molecular
mechanisms of these modulations and the physiological role of PARP have
not been clearly elucidated.
Mice and fruit flies became the most useful animals to analyze the
physiological functions of the target protein because of the
accumulated knowledge in developmental biology and also recently advanced and sophisticated techniques to make knockout and transgenic animals (23, 24). Many mutants of Drosophila have been
isolated, and their phenotypes are characterized (25). Disruption of
the target gene by P-element transfer or mutagenesis by
-irradiation and chemical mutagens has been used to analyze gene function.
Recently, cleavage of PARP by caspases, ICE family proteases, during
apoptosis has been reported (21). Overexpression of the DNA-binding
domain of PARP in mammalian cells, as a dominant negative mutant,
modulated sensitivity in apoptosis to chemical treatments (26, 27).
However, the biological significance of PARP and degradation of PARP in
apoptotic cell death is unclear. During development, removal of
unnecessarily cells by programmed cell death is crucial for normal
development of animals. Programmed cell death is controlled strictly
during development (28-30). Gene expression of PARP and its
localization in embryos during embryogenesis have not been described,
and the role of PARP in development is unknown. It is important to know
the involvement of PARP in development for understanding biological
functions of PARP in vivo. In this study, we determined the
organization of the PARP gene, and described the temporal
changes in gene expression during Drosophila development and
the spatial distribution of the PARP expression in embryos by mRNA in situ hybridization.
 |
EXPERIMENTAL PROCEDURES |
Screening of the Drosophila Genomic Library--
The
Drosophila genomic library EMBL-3 SP6/T7
(CLONTECH) was screened using a 0.4-kb cDNA
fragment from nt +2254 to +2627 (the nt +1 corresponds to the first
nucleotide of translation initiation codon of D. PARP
cDNA (7)) and pD-5', a 1.3-kb EcoRI-XbaI
fragment (nt +117 to +1078 of cDNA) as probes. A full-length
cDNA was also used to screen cosmid libraries (Promega, Madison,
WI). Recombinants grown on agar plates were transferred onto two
replica filters of nitrocellulose. Filter lifts were hybridized with
probes under standard conditions (31) and exposed to a x-ray film.
Restriction Mapping of Genomic Clones--
Cosmid and phage
clones were subjected to mapping of restriction sites with complete
restriction digestion and partial digestion using cosmid mapping kit
(Takara, Kyoto, Japan). Overlapping of clones were confirmed by
hybridizing each other.
DNA Sequencing--
Restriction fragments of phage clones
containing exons were subcloned into pBluescript II KS
(Stratagene,
La Jolla, CA), and the deletion plasmids were prepared. Sequencing was
performed by the dideoxy chain termination method using a sequencing
kit (Life Technologies, Inc.; Applied Biosystems, Foster City, CA). Sequences were analyzed by MACMOLLY-TETRA (Soft Gene GmbH, Berlin, Germany) and GCG (Genome Computer Group Inc., Madison, WI).
DNA Extraction and Southern Blot Analysis--
The genomic DNA
from adult flies of a wild type, Canton S, was extracted by a standard
method as described (32). Ten µg of DNA digested by restriction
enzymes were separated on a 0.8% agarose gel, then transferred onto a
nylon membrane (Hybond N+, Amersham Pharmacia Biotech, Buckinghamshire,
UK). A full-length cDNA for D. PARP labeled with
[
-32P]dCTP was hybridized and analyzed with a Fujix
BAS 2000 imaging analyzer (Fuji Photo Film, Tokyo, Japan). A fragment
amplified by polymerase chain reaction, which corresponds to exons 2 and 3 (from nt +169 to +562 of cDNA), was also used as a probe.
In Situ Hybridization to Polytene Chromosome--
Chromosome
in situ hybridization was carried out as described (33)
using biotinylated probes.
5' Rapid Amplification of cDNA End (RACE)--
To identify
the 5'-end of transcript of D. PARP, two µg of
poly(A)+ RNA prepared from Canton S embryos was subjected
to 5' RACE using 5' AmpliFINDER RACE kit
(CLONTECH). The reaction was performed according to
manufacturer's protocol. Primer Exon-2R (5'-AGCTGGGACGCTGGTTTTTA-3') and Exon-1R (5'-TTGAACCATGACAGCAATCCGAAGAGTATC-3') were used. The
products were subcloned into pCR II (CLONTECH), and
the nucleotide sequence was determined as described above.
DNA Transfection--
The plasmids pSK-CAT, pSV2-CAT with poly
linker of pBluescript, and pAc-CAT, pSK-CAT with Drosophila
actin 5C promoter (kind gifts from Dr. A. Matsukage, Aichi Cancer
Center Research Institute) were used. pEx1-1k-CAT contains a
KpnI-DraI fragment upstream of exon 1 (nt from
8 to
1, 234, +1 corresponds to the first nucleotide of the
initiation codon in exon 1 and the first base upstream of +1 is defined
as
1) in pSK-CAT. pEx1-2k-CAT has a ~2-kb
XbaI-DraI fragment upstream of exon 1. KC cells,
a Drosophila embryonic cell line, was kindly provided by Dr.
R. Ueda (Mitsubishi Kasei Institute of Life Sciences). The cells were
transfected with 15 µg of the CAT plasmids and 5 µg of the
-galactosidase plasmid (pRSV-
-gal, a kind gift from Dr. S. Ishii,
RIKEN) according to the method described by Chen and Okayama (34).
After 48-h incubation, cells were collected, and the cell lysates were
prepared. After centrifugation, the supernatant was used for the
following assay.
Chloramphenicol Acetyltransferase Assay (35)--
The cell
extract was incubated at 37 °C for 5 h in the reaction mixture
containing 0.25 µCi of
D-threo-[dichloroacetyl-1-14C]chloramphenicol
(Amersham Pharmacia Biotech) and 1 mM acetyl-CoA. This
mixture was extracted twice with ethyl acetate. The organic phase was
transferred to another tube and evaporated under vacuum. The residual
was dissolved in 30 µl of ethyl acetate, spotted on a silica gel
(Art. 5748, plastic sheets silica gel 60, Merck), and developed in a
thin-layer chromatography chamber containing chloroform:methanol (19:1,
v/v). The silica gel was exposed to a imaging plate for 30 min, and the
CAT activities were measured with a Fujix BAS 2000 imaging analyzer
(Fuji Photo Film). To standardize the CAT activity, the efficiency
of transfection was determined by a
-galactosidase assay as
described (36).
Northern Blotting--
Total RNA from Canton S was isolated as
described (37). Embryos collected at each 2 or 3 h AEL were
incubated at 25 °C. A probe of about 1-kb EcoRI fragment
from D. PARP cDNA (from nt +2008 to +2965) was used.
Hybridization was performed under standard conditions (31). The blot
was also probed with a 5'-radiolabeled oligonucleotide, rp49-3';
5'-TTGAATCCGGTGGGCAGCAT-3' from nt +699 to +680 of ribosomal protein
49, rp49 (X00848) (38). Autoradiographs of blots were analyzed with a
Fujix BAS 2000 imaging analyzer (Fuji Photo Film).
In Situ mRNA Hybridization of Embryos--
Whole mount
in situ hybridization of Drosophila embryos was
performed according to the procedure described by Tautz and Pfeifle (39). The single-stranded DNA probes prepared from D. PARP
cDNA by polymerase chain reaction using a single primer were
labeled using random prime DNA labeling kit (Boehringer Mannheim).
 |
RESULTS |
Cloning of the D. PARP Gene and Its Organization--
EMBL-3
SP6/T7 phage library was screened using probes of partial cDNAs for
D. PARP (7) and 12 clones covering all the coding regions
were obtained. To isolate overlapping clones, the pWE15 cosmid library
was screened. Using a full-length cDNA as a probe, 25 clones were
isolated from 1 × 106 recombinants. DNA fragments
containing the coding region were subcloned, and the nucleotide
sequences of the coding regions, including the exon-intron boundaries,
were determined (Table I). The
exon-intron boundaries had splicing sites that were located at
positions corresponding to amino acids 38, 86, 197, 375, and 565 of
Drosophila PARP. The organization of the D. PARP
gene is shown in Fig. 1. The DNA-binding
domain is encoded by exons 1, 2, 3, and 4. The first zinc finger was
encoded by exons 1 and 2, and the second zinc finger is included within
exon 3. Exon 4 contains a nuclear localization signal (40-42). The
auto-modification domain was encoded by exon 5, and the catalytic
domain was in exon 6, with a part in exon 5.

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Fig. 1.
Structure of D. PARP gene.
Six exons are shown as solid boxes. Restriction enzyme sites
are shown as follows: E, EcoRI; P;
PstI; X; XhoI. TATA
indicates the position of the TATA box of the D. PARP gene.
PARP cDNAs are shown with putative domain structures corresponding
to the DNA-binding, auto-modification, and catalytic domains.
Shaded boxes (Zn) are zinc finger motifs in the
DNA-binding domain. Part of the cosmid and phage clones is shown on the
bottom.
|
|
Compositions of exon-intron boundaries in Drosophila and
human PARP genes were compared. Although the zinc finger of
several zinc finger proteins is coded in a single exon, the first zinc finger of human PARP is split by an intron (43). This split site was
conserved between Drosophila and human PARP
genes. Exon 2 of the Drosophila gene encodes a half of the
first zinc finger and corresponds to exon 2 of the human
PARP gene. Drosophila exon 3 corresponds to exons
3 and 4 of the human gene. Drosophila exon 4 contains exons
5-8 of the human gene, and exon 5 corresponds to exons 9-12 of the
human gene, and exon 6 corresponds to exons 13-23 of the human
gene.
We mapped the restriction enzyme sites (EcoRI,
PstI, and XhoI) of the D. PARP gene
using overlapping cosmid clones. Fig. 2 (lanes 1-5) shows Southern blotting using a full-length
cDNA for PARP as a probes. The size of bands detected in
EcoRI, PstI, and XhoI digests
corresponded to the expected size from the restriction map (Fig. 1).
When the same blot was re-hybridized to exon 2 plus 3 specific probe, a
single band was detected at the expected sizes in each lane (Fig. 2,
lanes 6-10). The D. PARP gene was localized cytologically to the right arm of the third chromosome (3R) at position
of 81F by in situ polytene chromosome hybridization (data not shown).

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Fig. 2.
Southern blot analysis of
Drosophila genomic DNA. Ten µg of genomic DNA
digested with the following restriction enzymes was loaded in each
lane: EcoRI, lanes 1 and 6;
KpnI, lanes 2 and 7; PstI,
lanes 3 and 8; SalI, lanes
4 and 9; XhoI, lanes 5 and
10. The blot was probed with a full length of D.
PARP cDNA (7) in lanes 1-5 and with a DNA fragment
corresponding to exons 2 and 3 in lanes 6-10. DNA size
markers are shown.
|
|
Structure of the 5'-Noncoding Region of the D. PARP Gene--
We
determined the sequence of the putative 5' promoter and regulatory
region to 1280 bp upstream of the translation initiation start codon.
We also isolated the full extent of 5' portion of D. PARP
cDNA by 5' RACE to identify the transcriptional initiation site.
Nucleotide sequences of the 5' RACE fragments that have been subcloned
into plasmids were determined (data not shown). Three out of 10 clones
examined were completely identical. The 5'-end of these full-extended
clones, adenine nucleotide at
76 (+1 corresponds to the first
nucleotide of the initiation codon in exon 1, and the first base
upstream of +1 is defined as
1) from translation start codon (Fig.
3), suggested that the potential transcriptional initiation site in Drosophila PARP was 76 bp
upstream from the translation initiation site. The other seven clones
contained smaller fragments of the 5' portion of cDNA, possibly due
to incomplete reverse transcription. As shown in Fig.
4B, the 5'-flanking sequence of D. PARP had transcriptional activity in a
Drosophila embryonic cell line, KC cells. pEx1-1k-CAT, which
contains a 1-kb fragment upstream of exon 1, showed almost the same
activity as pEx1-2k-CAT, which contain a 2-kb fragment upstream of exon
1. A putative transcription initiation site, TATA and CCAAT boxes, and
putative binding sites for representative transcription factors (TF)
were identified (Fig. 3). A typical TATA box was found at
119. CCAAT
boxes were found at
132,
455, and
788. The CCAAT box at
788
matched to one of CP1 sites. Two sequence motifs, at
455 and
132,
were matched to conserved CCAAT box sequences that were found in
histone H2B genes in various species (44). Putative binding sites for CP2 and C/EBP were found. Two CP2-binding sequences were found at
808
and +48. Consensus sequences for C/EBP binding site (45) were at
331
and
169. The octamer motif was at
502. Zeste-, a
Drosophila TF that activates Ubx transcription
(46), binding sites were located at
1160 and
845. Binding sites of
H4TF-1, which was identified as a TF for human histone H4 promoter
(47), were found at
967,
869,
576, and
128. Binding sites of
HiNF-A, which also binds to human histone H4 promoter (48), were
located at
1122,
1114,
1094,
986,
876,
583,
506, and
81.

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Fig. 3.
Nucleotide sequence of the 5' region and
representative TF-binding sites of the D. PARP gene. A
TATA box, CCAAT boxes, an octamer motif, and translation start codon
are boxed. Consensus sequences for the TF-binding elements
are indicated as solid bars. A potential transcription
initiation site is indicated by an arrow with closed
arrowhead. The positions of primers used for 5' RACE are indicated
as arrows with an open arrowhead. Nucleotide +1
corresponds to the first nucleotide of initiation codon, and the first
base upstream of +1 is defined as 1.
|
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Fig. 4.
Promoter activity of the 5' region of the
D. PARP gene. A, the positions of fragments used
are shown as arrows with a part of the genomic structure.
Open and closed boxes indicate the
nontranslatable region and the coding region, respectively. Restriction
enzyme sites are shown as follows: B, XbaI;
E, EcoRI; D, DraI;
K, KpnI; and X, XhoI.
TATA indicates the position of the TATA box. B,
percentages of acetylated chloramphenicol (Cm) per total
chloramphenicol are indicated. Lane 1, pEx1-2k-CAT;
lane 2, pEx1-1k-CAT; lane 3, pAc-CAT as a
positive control; lane 4, pSK-CAT as a negative
control.
|
|
Expression of PARP mRNA during Drosophila Development--
The
amount of PARP mRNA during development is shown in Fig.
5. The PARP mRNA gave a
3.2-kb band, except in the larval stages (Fig. 5A, lane 9 and 10). Changes of the PARP mRNA level
during development, standardized by rp49, are shown in Fig.
5B. PARP expression was at a high level in
embryos 0-2 h AEL (Fig. 5B, lane 1) and decreased to 20%
at 6-8 h (lane 4), later showing a slight increase at 8-10
h (lane 5). In these stages, a minor band of 2.6 kb was
observed in addition to a major 3.2-kb band of PARP
mRNA. A cDNA clone, which lacks the auto-modification domain by
alternative splicing of exon 5, was
isolated.2 A smaller mRNA corresponds
to this alternative form of PARP. The amount of PARP
mRNA in pupae (lane 11) was about 20%, and in adults
(lane 12) 30%, of 0-2-h embryo levels.

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Fig. 5.
Expression of the D. PARP gene in
the developmental stages. Lane 1, 0-2 h AEL; lane
2, 2-4 h AEL; lane 3, 4-6 h AEL; lane 4,
6-8 h AEL; lane 5, 8-10 h AEL; lane 6, 10-12 h
AEL; lane 7, 12-15 h AEL; lane 8, 15-18 h AEL;
lane 9, first instar larvae; lane 10, third
instar larvae; lane 11, pupae; lane 12, adults.
A, twenty µg of total RNA were analyzed by Northern blot
using D. PARP cDNA as a probe as described under
"Experimental Procedures." The PARP and rp49 transcripts were
observed at 3.2 and 0.5 kb, respectively. B, relative
radioactivity is shown. The PARP expression levels were
standardized by intensity of rp49.
|
|
Spatial distribution of the mRNA during embryogenesis is shown
in Fig. 6. PARP mRNA was
distributed uniformly over the cleavage and blastodermal embryos (Fig.
6, A and B), but was indiscernible in pole cells,
the germ line progenitor, of the cellular blastodermal embryos (data
not shown). Later during embryogenesis, the mRNA was distributed in
almost all cells of the embryos. A large amount of PARP
mRNA accumulated in an unidentified cell type dispersed around the
central nervous system at stage 14-15 (Fig. 6D) and in the
cells forming the anal plate of stage 16 embryos (data not shown).
During oogenesis, PARP mRNA was detectable in the nurse
cells of the early stage 10 egg chambers and accumulated in the oocytes
of the egg chambers at stage 11-12 (Fig. 6H).

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Fig. 6.
The distribution of PARP
transcripts during embryogenesis and RNA expression in ovaries.
Lateral views of whole mount mRNA in situ hybridization
of embryos are shown (A-F). Antisense probe was used in
A-E, G, and H, and sense probe was
used in F as negative control. A and F
are stage 1; B is stage 4; C is stage 13;
D is stage 13-14; E is stage 16. Accumulation of
PARP mRNA in ovaries is shown in G and
H. Scale bars, 100 µm.
|
|
 |
DISCUSSION |
We isolated overlapping cosmid clones covering almost the entire
PARP gene. The PARP gene spanned more than 60 kb
in length and was composed of six coding exons separated by five
introns. The human PARP gene has 23 exons and is 43 kb in
length (43). In Drosophila, the auto-modification domain was
encoded in a single exon, and the catalytic domain is almost all
encoded by exon 6. Thus, organization of exons of the D. PARP gene seems to correspond to its functional domains. The size
of bands in genomic Southern blot analysis using a full-length cDNA
and exon-specific probes was explained by the expected size from cosmid
mapping. These results indicate that D. PARP gene is a
single copy per haploid genome. The D. PARP gene was mapped
to 81F of third chromosome. This locus is nearby centromeric
heterochromatin regions of chromosome III.
The regulatory region of the D. PARP gene showed
transcriptional activity in KC cells. The promoter region of the
D. PARP gene has a TATA box and three CCAAT boxes and an
octamer motif, while mammalian PARP genes have no typical
TATA boxes, but have GC-rich sequences (49, 50). Putative AP-1 binding
sites were found in the D. PARP promoter, and induction of
PARP expression by
12-O-tetradecanoylphorbol-13-acetate treatment has been
reported in mammalian cells (51). However, D. PARP gene
expression did not increase by
12-O-tetradecanoylphorbol-13-acetate treatment of KC cells
(data not shown).
Expression of PARP mRNA was at a high level in early embryos and
distributed uniformly in the embryos, except for pole cells. Accumulation of PARP mRNA in oocytes and in embryos
immediately after oviposition indicates that PARP mRNA
in early embryos might be of maternal origin. PARP is abundant in
nuclei of mammalian cells and its mRNA increases at the S phase of
cell cycle (52). It is speculated that PARP may be involved in nuclear
or cell division in the early embryo. A slight increase in the amount of PARP mRNA in embryos at 8-19 h AEL (Fig. 5) is
possibly due to zygotic expression of the PARP gene.
PARP mRNA accumulated in an unidentified cell type
dispersed around the central nervous system in embryos at stage 14-15.
During these stages, programmed cell death occurred around the central
nervous system (53). It is interesting that no PARP transcript was
detected in the first or third instar. DNA synthesis occurred
extensively during the larval stage, but was not accompanied by mitosis
and cytokinesis (54).
Further investigations on the role of PARP in developmental processes
will be possible by the use of P-insertion mutants and transgenic flies
with ectopic expression of PARP. Targeted expression of PARP in the eye
imaginal disc induced aberrant development of eyes in
Drosophila.3 The
role of PARP in cell cycle, cell differentiation, and apoptosis in
compound eyes can be examined by these transgenic flies. Additionally, it should now be possible to identify functionally related targets by
the use of genetic methods and analysis of suppressor and enhancer mutants and elucidate the signaling pathway.
 |
ACKNOWLEDGEMENTS |
We thank H. Masuda, K. Maeshima, and Y. Yoshida for technical help in sequencing or in situ
hybridization. We also thank Dr. Y. Masuho and H. Okano for helpful
comments and discussion.
 |
FOOTNOTES |
*
This work was supported in part by grants-in-aid for
scientific research, cancer research, and Tsukuba project research from the Ministry of Education, Science, Sports and Culture, for cancer research from Sagawa Foundation, and for a Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health and Welfare of
Japan.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 nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF051544-AF051548.
¶
To whom correspondence should be addressed: Dept. of
Biochemistry and Molecular Oncology, Institute of Basic Medical
Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305, Japan. Tel.: 81-298-53-3272; Fax: 81-298-53-3271; E-mail:
kzuchida{at}md.tsukuba.ac.jp.
1
The abbreviations used are: PARP,
poly(ADP-ribose) polymerase; AEL, after egg laying; bp, base pair(s);
D. PARP, Drosophila poly(ADP-ribose) polymerase;
kb, kilobase(s); nt, nucleotide(s); RACE, rapid amplification of
cDNA end; TF, transcription factor; CAT, chloramphenicol
acetyltransferase.
3
M. Uchida, S. Hanai, K. Sawamoto, H. Okano, M. Miwa, and K. Uchida, unpublished observation.
2
T. Kawamura, S. Hanai, M. Uchida, M. Miwa, and
K. Uchida, unpublished data.
 |
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