Genomic Organization of Drosophila Poly(ADP-ribose) Polymerase and Distribution of Its mRNA during Development*

Shuji HanaiDagger , Masahiro UchidaDagger , Satoru Kobayashi§, Masanao MiwaDagger , and Kazuhiko UchidaDagger

From the Dagger  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
Top
Abstract
Introduction
Procedures
Results
Discussion
References

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
Top
Abstract
Introduction
Procedures
Results
Discussion
References

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 beta -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 gamma -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
Top
Abstract
Introduction
Procedures
Results
Discussion
References

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 [alpha -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 beta -galactosidase plasmid (pRSV-beta -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 beta -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
Top
Abstract
Introduction
Procedures
Results
Discussion
References

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. 

                              
View this table:
[in this window]
[in a new window]
 
Table I
Exon-intron organization of D. PARP gene


View larger version (13K):
[in this window]
[in a new window]
 
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).


View larger version (77K):
[in this window]
[in a new window]
 
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.


View larger version (75K):
[in this window]
[in a new window]
 
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.


View larger version (26K):
[in this window]
[in a new window]
 
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.


View larger version (23K):
[in this window]
[in a new window]
 
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).


View larger version (102K):
[in this window]
[in a new window]
 
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
Top
Abstract
Introduction
Procedures
Results
Discussion
References

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.

    REFERENCES
Top
Abstract
Introduction
Procedures
Results
Discussion
References

  1. Althaus, F. R., and Richter, C. (1987) Mol. Biol. Biochem. Biophys. 37, 1-237[Medline] [Order article via Infotrieve]
  2. Miwa, M., and Uchida, K. (1992) in The Post-translational Modification of Proteins: Roles in Molecular and Cellular Biology (Tuboi, S., Taniguchi, N., and Katunuma, N., eds), pp. 171-182, Japan Scientific Societies, Tokyo
  3. de Murcia, G., and Ménissier-de Murcia, J. (1994) Trends Biochem. Sci. 19, 172-176[CrossRef][Medline] [Order article via Infotrieve]
  4. Lindahl, T., Satoh, M. S., Poirier, G. G., and Klungland, A. (1995) Trends Biochem. Sci. 20, 405-411[CrossRef][Medline] [Order article via Infotrieve]
  5. Ozawa, Y., Uchida, K., Uchida, M., Ami, Y., Kushida, S., Okada, N., and Miwa, M. (1993) Biochem. Biophys. Res. Commun. 193, 119-125[CrossRef][Medline] [Order article via Infotrieve]
  6. Uchida, K., Uchida, M., Hanai, S., Ozawa, Y., Ami, Y., Kushida, S., and Miwa, M. (1993) Gene (Amst.) 137, 293-297[Medline] [Order article via Infotrieve]
  7. Uchida, K., Hanai, S., Ishikawa, K., Ozawa, Y., Uchida, M., Sugimura, T., and Miwa, M. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 3481-3485[Abstract]
  8. Masutani, M., Nozaki, T., Hitomi, Y., Ikejima, M., Nagasaki, K., de Prati, A. C., Kurata, S., Natori, S., Sugimura, T., and Esumi, H. (1994) Eur. J. Biochem. 220, 607-614[Abstract]
  9. Uchida, K., and Miwa, M. (1994) Mol. Cell. Biochem. 138, 25-32[Medline] [Order article via Infotrieve]
  10. Shall, S. (1984) Adv. Radiat. Biol. 11, 1-69
  11. Molinete, M., Vermeulen, W., Bürkle, A., Ménissier-de Murcia, J., Küpper, J. H., Hoeijmakers, J. H., and de Murcia, G. (1993) EMBO J. 12, 2109-2117[Abstract]
  12. Bürkle, A., Meyer, T., Hilz, H., and zur Hausen, H. (1987) Cancer Res. 47, 3632-3636[Abstract]
  13. Smith, J. A., and Stocken, L. A. (1975) Biochem. J. 147, 523-529[Medline] [Order article via Infotrieve]
  14. Bhatia, M., Kirkland, J. B., and Meckling-Gill, K. A. (1996) Cell Growth Differ. 7, 91-100[Abstract]
  15. Kun, E., Kirsten, E., Milo, G. E., Kurian, P., and Kumari, H. L. (1983) Proc. Natl. Acad. Sci. U. S. A. 80, 7219-7223[Abstract]
  16. Borek, C., Morgan, W. F., Ong, A., and Cleaver, J. E. (1984) Proc. Natl. Acad. Sci. U. S. A. 81, 243-247[Abstract]
  17. Lubet, R. A., McCarvill, J. T., Schwartz, J. L., Putman, D. L., and Schechtman, L. M. (1986) Carcinogenesis 7, 71-75[Abstract]
  18. Takahashi, S., Ohnishi, T., Denda, A., and Konishi, Y. (1982) Chem. Biol. Interact. 39, 363-368[Medline] [Order article via Infotrieve]
  19. Nakagawa, K., Utsunomiya, J., and Ishikawa, T. (1988) Carcinogenesis 9, 1167-1171[Abstract]
  20. Kaufmann, S. H., Desnoyers, S., Ottaviano, Y., Davidson, N. E., and Poirier, G. G. (1993) Cancer Res. 53, 3976-3985[Abstract]
  21. Lazebnik, Y. A., Kaufmann, S. H., Desnoyers, S., Poirier, G. G., and Earnshaw, W. C. (1994) Nature 371, 346-347[CrossRef][Medline] [Order article via Infotrieve]
  22. Tewari, M., Quan, L. T., O'Rourke, K., Desnoyers, S., Zeng, Z., Beidler, D. R., Poirier, G. G., Salvesen, G. S., and Dixit, V. M. (1995) Cell 81, 801-809[Medline] [Order article via Infotrieve]
  23. Capecchi, M. R. (1989) Science 244, 1288-1292[Medline] [Order article via Infotrieve]
  24. Kühn, R., Schwenk, F., Aguet, M., and Rajewsky, K. (1995) Science 269, 1427-1429[Medline] [Order article via Infotrieve]
  25. Lindsley, D. L., and Zimm, G. G. (1992) The Genome of Drosophila melanogaster, Academic Press, San Diego, CA
  26. Küpper, J. H., Müller, M., Jacobson, M. K., Tatsumi-Miyajima, J., Coyle, D. L., Jacobson, E. L., and Bürkle, A. (1995) Mol. Cell. Biol. 15, 3154-3163[Abstract]
  27. Schreiber, V., Hunting, D., Trucco, C., Gowans, B., Grunwald, D., de Murcia, G., and Ménissier-de Murcia, J. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 4753-4757[Abstract]
  28. Ellis, R. E., Yuan, J. Y., and Horvitz, H. R. (1991) Annu. Rev. Cell Biol. 7, 663-698[CrossRef]
  29. Steller, H. (1995) Science 267, 1445-1449[Medline] [Order article via Infotrieve]
  30. Jacobson, M. D., Weil, M., and Raff, M. C. (1997) Cell 88, 347-354[Medline] [Order article via Infotrieve]
  31. Sambrook, J., Fritsch, E. F., and Maniatis, T. (1989) Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
  32. Ashburner, M. (1989) Drosophila: A Laboratory Manual, pp. 106-107, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
  33. Engels, W. R., Preston, C. R., Thompson, P., and Eggleston, W. B. (1986) Focus 8, 6-8
  34. Chen, C., and Okayama, H. (1987) Mol. Cell. Biol. 7, 2745-2752[Medline] [Order article via Infotrieve]
  35. Gorman, C. M., Moffat, L. F., and Howard, B. H. (1982) Mol. Cell. Biol. 2, 1044-1051[Medline] [Order article via Infotrieve]
  36. Herbomel, P., Bourachot, B., and Yaniv, M. (1984) Cell 39, 653-662[Medline] [Order article via Infotrieve]
  37. Chomczynski, P., and Sacchi, N. (1987) Anal. Biochem. 162, 156-159[CrossRef][Medline] [Order article via Infotrieve]
  38. O'Connell, P. O., and Rosbash, M. (1984) Nucleic Acids Res. 12, 5495-5513[Abstract]
  39. Tautz, D., and Pfeifle, C. (1989) Chromosoma (Berl.) 98, 81-85[Medline] [Order article via Infotrieve]
  40. Uchida, K., Morita, T., Sato, T., Ogura, T., Yamashita, R., Noguchi, S., Suzuki, H., Nyunoya, H., Miwa, M., and Sugimura, T. (1987) Biochem. Biophys. Res. Commun. 148, 617-622[Medline] [Order article via Infotrieve]
  41. Alkhatib, H. M., Chen, D., Cherney, B., Bhatia, K., Notario, V., Giri, C., Stein, G., Slattery, E., Roeder, R. G., and Smulson, M. E. (1987) Proc. Natl. Acad. Sci. U. S. A. 84, 1224-1228[Abstract]
  42. Schreiber, V., Molinete, M., Boeuf, H., de Murcia, G., and Ménissier-de Murcia, J. (1992) EMBO J. 11, 3263-3269[Abstract]
  43. Auer, B., Nagl, U., Herzog, H., Schneider, R., and Schweiger, M. (1989) DNA (N. Y.) 8, 575-580[Medline] [Order article via Infotrieve]
  44. Wells, D. E. (1986) Nucleic Acids Res. 14, (suppl.) r119-r149
  45. Johnson, P. F., Landschulz, W. H., Graves, B. J., and McKnight, S. L. (1987) Genes Dev. 1, 133-146[Abstract]
  46. Biggin, M. D., and Tjian, R. (1989) Trends Genet. 5, 377-383[CrossRef][Medline] [Order article via Infotrieve]
  47. Dailey, L., Hanly, S. M., Roeder, R. G., and Heintz, N. (1986) Proc. Natl. Acad. Sci. U. S. A. 83, 7241-7245[Abstract]
  48. van Wijnen, A. J., Stein, J. L., and Stein, G. S. (1987) Nucleic Acids Res. 15, 1679-1698[Abstract]
  49. Ogura, T., Nyunoya, H., Takahashi-Masutani, M., Miwa, M., Sugimura, T., and Esumi, H. (1990) Biochem. Biophys. Res. Commun. 167, 701-710[Medline] [Order article via Infotrieve]
  50. Potvin, F., Thibodeau, J., Kirkland, J. B., Dandenault, B., Duchaine, C., and Poirier, G. G. (1992) FEBS Lett. 302, 269-273[CrossRef][Medline] [Order article via Infotrieve]
  51. Yokoyama, Y., Kawamoto, T., Mitsuuchi, Y., Kurosaki, T., Toda, K., Ushiro, H., Terashima, M., Sumimoto, H., Kuribayashi, I., Yamamoto, Y., Maeda, T., Ikeda, H., Sagara, Y., and Shizuta, Y. (1990) Eur. J. Biochem. 194, 521-526[Abstract]
  52. Menegazzi, M., Gerosa, F., Tommasi, M., Uchida, K., Miwa, M., Sugimura, T., and Suzuki, H. (1988) Biochem. Biophys. Res. Commun. 156, 995-999[Medline] [Order article via Infotrieve]
  53. Abrams, J. M., White, K., Fessler, L. I., and Steller, H. (1993) Development (Camb.) 117, 29-43[Abstract/Free Full Text]
  54. Lehner, C. F., and Lane, M. E. (1997) J. Cell Sci. 110, 523-528[Abstract/Free Full Text]


Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.