Mutagenesis, Vol. 16, No. 4, 365-368,
July 2001
© 2001 UK Environmental Mutagen Society/Oxford University Press
Ionizing radiation damage repair: a role for topoisomerases?
Department of Cellular Biology, Faculty of Biology, University of Seville, Avenida Reina Mercedes 6, 41012 Seville, Spain
Abstract
In parallel with the developing field of DNA topoisomerase poisons in tumor chemotherapy, the basic features of these nuclear enzymes have been unfolded. The role of topoisomerases in fundamental processes involving DNA metabolism has been shown to outpace by far the initial expectations. While DNA topoisomerases are involved in relaxation of chromatin to relieve tension during DNA replication and transcription, as well as for recombinational processes and chromosome segregation and condensation, the possible role, either direct or indirect, of these enzymes in DNA repair is still a matter of discussion. In this survey the possible relationship of topoisomerases with the repair of ionizing radiation damage in mammalian cells is considered, on the basis of attractive `clues' and in the light of a number of observations.
Introduction
Following the pace of new and increasingly more powerful biochemical and genetic approaches recent years have witnessed the unfolding of the basic features of DNA topoisomerases (topos). These conserved ubiquitous nuclear enzymes regulate DNA topology through concerted breakage and rejoining of the molecule during replication, transcription and recombination and facilitate correct chromosome organization and segregation (Wang, 1996
). There are two classes of topoisomerases according to their catalytic mechanisms. Type I monomeric enzymes, which do not require ATP, act by forming a transient single-strand break (ssb) through which relaxation is achieved. Type II enzymes, usually ATP-dependent dimeric enzymes, are able to make a double-strand break (dsb), creating a DNA-linked protein gate through which another intact duplex passes (Wang, 1985). Both type I and type II enzymes are proficient in relaxing supercoiled DNA, while only type II can decatenate intertwined DNA molecules. This latter feature makes type II topoisomerases necessary for separation of daughter DNA molecules after replication. So far, four different topoisomerases have been reported to be present in higher eukaryotes, namely topos I and III, which belong to type I, and topos II
and IIß, two isoforms belonging to the type II family. Whereas the biological functions of topos III and IIß are poorly understood, many investigations have dealt with the roles of topo I and topo II.
Both topo I and topo II function during replication to relieve tension generated as a result of replication fork progression. Topo I may have a more specific role in transcription (transcriptionally active regions are enriched in topo I) and topo II in segregation of daughter chromatids after DNA replication and in the processes of chromatin condensation and mitotic segregation (Wang, 1996).
While convincing evidence has been presented on the direct role played by DNA topoisomerases in transcription and replication, the possible direct or indirect involvement of these enzymes in DNA repair is still a matter of controversy (Downes and Johnson, 1988; Friedberg et al., 1995). The hypothesis was initially based on observations on the effects of the topo II inhibitor novobiocin on the repair of UV damage (Collins and Johnson, 1979). In this survey we will focus on the data available concerning ionizing radiation insult to DNA and the exciting evidence that seems to support the participation of topoisomerases in the so-called radiation response.
Why should topoisomerases be involved in DNA repair?
Background
Lesions induced by ionizing radiation in DNA range from base or nucleotide damage to ssb and dsb. DNA dsb have been considered to be the most important of these lesions for the cytotoxic effects of radiation, based on the correlation with cell killing and on the fact that efficient dsb-inducing agents, such as restriction enzymes, produce cellular effects similar to those induced by radiation (Bryant, 1984). While for the repair of base and nucleotide damage an excision repair process has to operate on DNA, dsb have to be repaired either by mainly error-free homologous recombination or by an error-prone DNA end joining process (Friedberg et al., 1995; Kanaar et al., 1998). The relative contributions of these two pathways to dsb repair differ in yeast and mammals, based on genetic and biochemical evidence (Kanaar et al., 1998).
Since ionizing radiation represents both a potential threat in the case of accidental exposure and an important tool in the therapy of many human tumours, a major challenge is to assess the relative contribution of the different dsb repair pathways to genomic stability and cell survival.
The question is: why should DNA topoisomerases play a role, either directly or indirectly, in the repair of radiation damage? Another interesting question is whether such a role should be a positive or negative one in terms of the final outcome of repair.
Evidence so far reported
We can consider two possible mechanisms: (i) a direct involvement of topoisomerases, either type I or type II or both, in the recombinational or DNA end joining repair processes described earlier or (ii) an indirect function of topoisomerases in preparative steps for opening of the chromatin for repair enzymes to gain access to radiation damaged DNA.
Concerning the recombinational pathway, there is strong evidence that topoisomerases (mainly topo II) are able to stimulate recombination both in vitro and in vivo (Halligan et al., 1982; Ikeda et al., 1982; Bullock et al., 1985; Ikeda, 1986; Bae et al., 1988; Zhu and Schiestl, 1996). While in most reports the recombination promoted by topoisomerases was of the illegitimate type (non-homologous), promotion of homologous error-free recombination cannot be ruled out. No experimental evidence has been presented so far linking this putative recombinational mechanism mediated by topoisomerases with radiation damage repair, so it remains only an interesting hypothesis.
An opening of the chromatin, on the other hand, as achieved through topoisomerase catalytic activity, is likely necessary to facilitate access of repair enzymes, such as those functioning in excision repair of base and nucleotide damage (glycosylases, endonucleases, exonucleases, polymerases and ligases) to damaged sites in DNA. Concerning radiation damage, however, it can be argued that DNA dsb could lead to unwinding of DNA in the vicinity, making the activity of topoisomerases unnecessary. The above notwithstanding, site-specific DNA relaxation as achieved by topoisomerases, in comparison with radiation-induced randomly distributed DNA breaks, might be necessary.
Focusing on a very specific example, it is worth mentioning the reported functional interaction between the yeast rad12/rqh gene homologue of the Escherichia coli RecQ DNA helicase and topos II and III (Maftahi et al., 1999). This seems very important given the role of RecQ-like helicases in genetic stability and taking into account the reported homology with human genes encoding for Werner and Bloom's syndrome helicases (Lebel and Leder, 1998; Harmon et al., 1999; Maftahi et al., 1999; Frei and Gasser, 2000). However, this possible indirect role of topoisomerases resulting in chromatin relaxation in connection with DNA repair is still an open question.
Let us now consider the possibility of a negative role played by topoisomerases in the repair of radiation damage to DNA that might result in mutation and cell death should the enzymes be active in spite of radiation damage. A characteristic feature of the cellular response to ionizing radiation exposure is inhibition of replicon initiation. Interestingly, the best characterized human hereditary radiosensitive syndrome, ataxia telangiectasia (AT) shows `radioresistant DNA synthesis', i.e. a failure to inhibit replicon initiation in spite of irradiation (Painter and Young, 1980), and has been reported as defective in DNA topo II (Lavin and Singh, 1990). Also, the Chinese hamster radiosensitive mutant irs2 shows a phenotype similar to AT concerning a radioresistant S phase (Debenham et al., 1987; Jones et al., 1990) and, interestingly, exhibits a similar hypersensitivity to topoisomerase inhibitors (Caporossi et al., 1993; Jones et al., 1993; Elli et al., 1996).
Since topoisomerase activity is needed for replication, inhibition of topoisomerases might prevent replication in irradiated S phase cells, avoiding DNA synthesis upon a damaged template. A potential mechanism for radiation damage to `switch off' topoisomerase activity would be through the well-known enhancement of the activity of poly(ADP) ribosyltransferase (PARP) in response to DNA strand breaks. Isolated enzyme studies have shown that topoisomerases are substrates for PARP and poly(ADP) ribosylation is associated with a reduction in topoisomerase catalytic activity (Ferro et al., 1983; Jongstra-Bilen et al., 1983).
However, there is no evidence for inhibition of topoisomerases in irradiated cells and results obtained in our laboratory using synchronous cultured Chinese hamster cells indicate just the opposite, i.e. an increased activity of DNA topoisomerases after ionizing radiation treatment in repair-proficient cells (Pastor et al., 1999).
Studies in yeast have shown that topoisomerases (both I and II) not only promote, as mentioned earlier, but could also suppress recombination. Nitiss and Wang (1988) reported that anti-tumour drugs that poison DNA topo I and II activities induce a high yield of homologous recombination, although a possible explanation could be that the drugs freeze the topoisomerase–DNA complex, which amounts to covalently bound protein next to a break in the DNA, a potentially very dangerous and recombinogenic lesion (Larsen and Gobert, 1999; Russell et al., 2000). Nevertheless, it has been reported that mitotic recombination within the Saccharomyces cerevisiae rDNA cluster is suppressed by the combined action of topos I and II (Christman et al., 1988).
The key question: involvement in radiation repair or simply participating in the response to radiation stress?
While no overwhelming evidence has been presented to date showing that topoisomerase activity does influence, either positively or negatively, the final outcome of enzymatic repair of radiation damage in DNA, the main body of data seems to support the idea that either their activity or expression, or both, are modulated after ionizing radiation exposure.
A classical approach to the question could be the use of inhibitors of topoisomerases, to see whether their impairment has any effect on DNA repair. Nevertheless, the commonly used topoisomerase `poisons' are not true catalytic inhibitors but instead stabilize the enzyme–DNA complex (the so-called `cleavable complex'), giving rise to DNA strand breaks. This complicates interpretation of results from experiments combining topoisomerase poisons with ionizing radiation. The more recently reported `true' catalytic inhibitors of topo II (Funayama et al., 1993; Lopez et al., 1994; Leliévre et al., 1995; Hamatake et al., 1997; Hashimoto et al., 1997), which do not induce DNA damage, open a promising new way to assess a possible modulation of radiation damage repair by topoisomerase inhibition.
Special attention, on the other hand, has been focused on the variations in topoisomerase activities and levels after X- and 
-ray treatment of cultured mammalian cells as well as on a possible correlation between abnormalities of topoisomerases and radiation sensitivity or resistance observed in mutants of human and rodent origin (Zdzienicka, 1995).
Reports from different laboratories have been presented showing increased activities and/or levels of topoisomerases, mainly topo I, in human cells after exposure to ionizing radiation (Johnstone and McNerney, 1985; Thielmann and Popanda, 1998; Thielmann et al., 1999). Contrasting with observations in asynchronous human peripheral blood lymphocytes and cultured lymphoblastoid cells (Johnstone and McNerney, 1985), down-regulation of topo I in confluence-arrested hamster and human cells following ionizing radiation has been reported (Boothman et al., 1994) and a possible involvement of PARP was proposed. An explanation for these conflicting results concerning the topo I response to ionizing radiation is not at hand.
Topoisomerase levels and activities can fluctuate depending upon cell cycle stage, mainly for topo II. Topo II mRNA accumulates during late S phase and is subsequently degraded during M/early G1 (Goswami et al., 1996). In our laboratory we have recently made use of synchronized cultures of the Chinese hamster ovary radiosensitive mutant EM9 (Thompson et al., 1982) and its parental line AA8, which shows a normal response to ionizing radiation, to assess topoisomerase activities and levels shortly after X-ray exposure. Topo I and topo II activities in nuclear extracts were assayed as the ability to relax supercoiled plasmid DNA and to decatenate kinetoplast DNA, respectively. While dramatic increases in topo I and topo II activities in response to ionizing radiation exposure were observed in the repair-proficient AA8 parental cells, the radiosensitive EM9 cells did not show any similar response (Pastor et al., 1999). Such a rapid enhancement of topoisomerase activity, mainly topo I, must necessarily be ascribed to post-translational modification, but nuclear accumulation was also observed later on, detected by in situ immunological analysis of topoisomerases (Pastor et al., 1999).
p53 protein is one of the most important regulators of cell cycle progression in mammals, with an apparent dual role in induction of cell cycle arrest following genotoxic insult and in regulation of the apoptotic cell death pathway. Interestingly, this radiation-activated oncogene suppressor protein has been shown to be able to modulate the activity of DNA topoisomerases by transcriptional regulation (Sandri et al., 1996; Wang et al., 1997). For example, it has been reported that wild-type p53 regulates the minimal promoter of the human topo II gene, by acting on the basal transcription machinery, implicating topo II as one of the several downstream targets for p53-dependent regulation of cell cycle progression in human cells (Sandri et al., 1996).
An inverse correlation between radiation sensitivity measured as loss of clonogenic survival and DNA supercoiling ability within chromatin loops was observed in the XR-1 (dsb repair-deficient, radiosensitive) Chinese hamster ovary cells compared with the wild-type and a radioresistant cell line (Malyapa et al., 1994), with the degree of inhibition of loop rewinding being greater in the radiation-sensitive cells compared with the radiation-resistant cells.
Concluding remarks
Given their mechanism of action as well as other considerations, the attractive hypothesis of a direct or indirect involvement of type I or type II topoisomerases or both in the multi-enzymatic repair processes dealing with radiation damaged DNA has been proposed. There are two possible ways by which topoisomerases could play a role. Firstly, the active participation of topoisomerases could be essential to carry out chromatin relaxation, which in turn might facilitate access of repair enzymes to lesions in the DNA. This would be a preparatory role, without any direct participation of topoisomerases in radiation repair. Alternatively, these nuclear enzymes might play a direct role in repair, most likely through their involvement in recombinational mechanisms.
Though attractive, these proposals have to be treated with caution. Treatment of cells with ionizing radiation stimulates transcription of a large set of genes, the so-called DNA damage response genes, such as p53, and a specific role for topo I in transcriptional initiation and elongation is agreed upon (Wang, 1996), while it has also been proposed that topo II may also be involved in transcription (Thielmann and Popanda, 1998). Although the relationship could, of course, be circumstantial, it is well known that preferential repair activity takes place in actively transcribing regions of the genome (Bohr, 1988).
Future investigations will answer the question beyond any doubt as to whether topoisomerases are necessary for repair or are simply `bystanders' whose activity increases with DNA damage, in the wake of the cellular response.
Acknowledgments
The authors are greatly indebted to M.A. Ledesma for her excellent technical assistance. This work has been partly funded by grants from the Spanish Ministry of Education and Culture (PB96-1328), the European Union (FI4PCT950001) and the Junta de Andalucía (Spain).
Notes
1 To whom correspondence should be addressed. Tel: +34 95 4557039; Fax: +34 95 4610261; Email: cortes{at}cica.es 
References
-
Bae,Y.S., Kawasaki,I., Ikeda,H. and Liu,L.F. (1988) Illegitimate recombination mediated by calf thymus DNA topoisomerase II in vitro. Proc. Natl Acad. Sci. USA, 85, 2076–2080.
Bohr,V.A. (1988) DNA repair and transcriptional activity in genes. J. Cell Sci., 90, 175–178.
Boothman,D.A, Fukunaga,N. and Wang,M. (1994) Down-regulation of topoisomerase I in mammalian cells following ionizing radiation. Cancer Res., 54, 4618–4626.
Bryant,P.E. (1984) Enzymatic restriction of mammalian cell DNA using PvuII and BamHI: evidence for the double-strand break origin of chromosomal aberrations. Int. J. Radiat. Biol., 46, 57–65.[Web of Science]
Bullock,P., Champoux,J.J. and Botchan,M. (1985) Association of crossover points with topoisomerase I cleavage sites: a model for nonhomologous recombination. Science, 230, 954–958.
Caporossi,D., Porfirio,B., Nicoletti,B., Palitti,F., Degrassi,F., De Salvia,R. and Tanzarella,C. (1993) Hypersensitivity of lymphoblastoid lines derived from ataxia telangiectasia patients to the induction of chromosomal aberrations by etoposide (VP-16). Mutat. Res., 290, 265–272.[Web of Science][Medline]
Christman,M.F., Dietrich,F.S. and Fink,G.R. (1988) Mitotic recombination in the rDNA of S. cerevisiae is suppressed by the combined action of DNA topoisomerases I and II. Cell, 55, 413–425.[Web of Science][Medline]
Collins,A.R.S. and Johnson,R. (1979) Novobiocin: an inhibitor of the repair of UV-induced but not X-ray-induced damage in mammalian cells. Nucleic Acids Res., 7, 1311–1320.
Debenham,P.G., Webb,M.B.T., Jones,N.J. and Cox,R. (1987) Molecular studies on the nature of the repair defect in ataxia-telangiectasia and their implications for cellular radiobiology. J. Cell Sci., suppl. 6, 177–184.
Downes,C.S. and Johnson,R.T. (1988) DNA topoisomerases and DNA repair. Bioessays, 8, 179–184.[Web of Science][Medline]
Elli,R., Chessa,L., Antonelli,A., Petrinelli,P., Ambra,R. And Marcucci,L. (1996) Effects of topoisomerase II inhibition in lymphoblasts from patients with progeroid and `chromosome instability' syndromes. Cancer Genet. Cytogenet., 87, 112–116.[Web of Science][Medline]
Ferro,A.M., Higgins,N.P. and Olivera,B.M. (1983) Poly(ADP-ribosylation) of a DNA topoisomerase. J. Biol. Chem., 258, 6000–6003.
Frei,C. and Gasser,S.M. (2000) RecQ-like helicases: the DNA replication checkpoint connection. J. Cell Sci., 113, 2641–2646.[Abstract]
Friedberg,E.C., Walker,G.C.and Siede,W. (1995) DNA Repair and Mutagenesis. ASM Press, Washington, DC.
Funayama,Y., Nishio,K., Takeda,Y., Kubota,N., Ohira,T., Ohmori,T., Ohta,S., Ogasawara,H., Hasegawa,S. and Saijo,N. (1993) Suramin inhibits the phosphorylation and catalytic activity of DNA topoisomerase II in human lung cancer cells. Anticancer Res., 13, 1981–1988.[Web of Science][Medline]
Goswami,P.C., Roti Roti,J.L. and Hunt,C.R. (1996) The cell cycle-coupled expression of topoisomerase II during S phase is regulated by mRNA stability and is disrupted by heat shock or ionizing radiation. Mol. Cell. Biol., 16, 1500–1508.[Abstract]
Halligan,B.D., Davis,J.L., Edwards,K.A. and Liu,L.F. (1982) Intra- and intermolecular strand transfer by HeLa DNA topoisomerase I. J. Biol. Chem., 257, 3995–4000.
Hamatake,M., Andoh,T. and Ishida,R. (1997) Effects of ICRF-193, a catalytic inhibitor of DNA topoisomerase II, on sister chromatid exchange. Anticancer Drugs, 8, 637–642.[Medline]
Harmon,F.G., DiGate,R.J. and Kowalczykowski,S.C. (1999) RecQ helicase and topoisomerase III comprise a novel DNA strand passage function: a conserved mechanism for control of DNA recombination. Mol. Cell, 3, 611–620.[Web of Science][Medline]
Hashimoto,S., Jing,Y., Kawazoe,N., Masuda,Y., Nakajo,S., Yoshida,T., Kuroiwa,Y. and Nakaya,K. (1997) Bufalin reduces the level of topoisomerase II in human leukemia cells and effects the cytotoxicity of anticancer drugs. Leukemia Res., 9, 875–883.
Ikeda,H. (1986) Bacteriophage T4 DNA topoisomerase mediates illegitimate recombination in vitro. Proc. Natl Acad. Sci. USA, 83, 922–926.
Ikeda,H., Aoki,K. and Naito,A. (1982) Illegitimate recombination mediated in vitro by DNA gyrase of Escherichia coli: structure of recombinant DNA molecules. Proc. Natl Acad. Sci. USA, 79, 3724–3728.
Johnstone,A. and McNerney,R. (1985) Changes in topoisomerase I activity after irradiation of lymphoid cells. Biosci. Rep., 5, 907–912.[Web of Science][Medline]
Jones,N.J., Stewart,S.A. and Thompson,L.H. (1990) Biochemical and genetic analysis of the Chinese hamster mutants irs1 and irs2 and their comparison to cultured ataxia telangiectasia cells. Mutagenesis, 5, 15–23.
Jones,N.J., Ellard,S., Waters,R. and Parry,E.M. (1993) Cellular and chromosomal hypersensitivity to DNA crosslinking agents and topoisomerase inhibitors in the radiosensitive Chinese hamster irs mutants: phenotypic similarities to ataxia telangiectasia and Fanconi's anaemia cells. Carcinogenesis, 14, 2487–2494.
Jongstra-Bilen,J., Ittel,M.-E., Niedergang,C., Vosberg,H.P. and Mandel,P. (1983) DNA topoisomerase I from calf thymus is inhibited in vitro by poly(ADP-ribosylation). Eur. J. Biochem., 136, 391–396.[Web of Science][Medline]
Kanaar,R., Hoeijmakers,J.H.J. and Van Gent,D.C. (1998) Molecular mechanisms of DNA double-strand break repair. Trends Cell Biol., 8, 483–489.[Web of Science][Medline]
Larsen,A.K. and Gobert,C. (1999) DNA topoisomerase I in oncology: Dr Jekyll or Mr Hyde? Pathol. Oncol. Res., 5, 171–178.[Medline]
Lavin,M.F. and Singh,S.P. (1990) Defective DNA topoisomerase II in ataxia-telangiectasia cells. Acta Biol. Hung., 41, 125–135.[Web of Science][Medline]
Lebel,M. and Leder,P. (1998) A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity. Proc. Natl Acad. Sci. USA, 95, 13097–13102.
Lelièvre,S., Benchokroun,Y. and Larsen,A.K. (1995) Altered topoisomerase I and II activities in suramin-resistant lung fibrosarcoma cells. Mol. Pharmacol., 47, 898–906.[Abstract]
Lopez,R., Peters,G.J., Smitskamp-Wilms,E., Virizuela,J.A., Van Ark-Otte,J., Pinedo,H.M. and Giaccone,G. (1994) In vitro sequence-dependent synergistic effect of suramin and camptothecin. Eur. J. Cancer, 11, 1670–1674.
Maftahi,M., Han,C.S., Langston,L.D., Hope,J.C., Zigouras,N. and Freyer,N. (1999) The top3(+) gene is essential in Schizosaccharomyces pombe and the lethality associated with its loss is caused by Rad12 helicase activity. Nucleic Acids Res., 27, 4715–4724.
Malyapa,R.S., Wright,W.D. and Roti,J.L.R. (1994) Radiation sensitivity correlates with changes in DNA supercoiling and nucleoid protein content in cells of three Chinese hamster cell lines. Radiat. Res., 140, 312–320.[Web of Science][Medline]
Nitiss,J. and Wang,J.C. (1988) DNA topoisomerase-targeting antitumour drugs can be studied in yeast. Proc. Natl Acad. Sci. USA, 85, 7501–7505.
Painter,R.B. and Young,B.R. (1980) Radiosensitivity in ataxia-telangiectasia, a new explanation. Proc. Natl Acad. Sci. USA, 77, 7315–7317.
Pastor,N., Piñero,J., Ortiz,T., Mateos,J.C., De Miguel,M. and Cortés,F. (1999) Topoisomerase activities and levels in irradiated Chinese hamster AA8 cells and in its radiosensitive mutant EM9. Int. J. Radiat. Biol., 75, 1035–1042.[Web of Science][Medline]
Russell,L.B., Hunsicker,P.R., Hack,A.M. and Ashley,T. (2000) Effect of the topoisomerase-II inhibitor etoposide on meiotic recombination in male mice. Mutat. Res., 464, 201–212.[Web of Science][Medline]
Sandri,M.I., Isaacs,R.J., Ongkeko,W.M., Harris,A.L., Hickson,I.D., Broggini,M. and Vikhanskaya,F. (1996) p53 regulates the minimal promoter of the human topoisomerase II alpha gene. Nucleic Acids Res., 24, 4464–4470.
Thielmann,H.W. and Popanda,O. (1998) Irradiation with ultraviolet light and -rays increases the level of DNA topoisomerase II in nuclei of normal and xeroderma pigmentosum fibroblasts. Int. J. Oncol., 12, 265–271.[Web of Science][Medline]
Thielmann,H.W., Popanda,O. and Staab,H.J. (1999) Subnuclear distribution of DNA topoisomerase I and Bax protein in normal and xeroderma pigmentosum fibroblasts after irradiation with UV light and gamma rays or treatment with topotecan. J. Cancer Res. Clin. Oncol., 125, 193–208.[Web of Science][Medline]
Thompson,L.H., Brookman,K.W., Dillehay,L.E., Carrano,A.V., Mazrimas,J.A., Mooney,C.L. and Minkler,J.L. (1982) A CHO-cell strain having hypersensitivity to mutagens, a defect in DNA strand-break repair and an extraordinary baseline frequency of sister-chromatid exchange. Mutat. Res., 95, 427–440.[Web of Science][Medline]
Wang,J.C. (1985) DNA topoisomerases. Annu. Rev. Biochem., 54, 665–697.[Web of Science][Medline]
Wang,J.C. (1996) DNA topoisomerases. Annu. Rev. Biochem., 65, 635–692.[Web of Science][Medline]
Wang,Q.J., Zambetti,G.P. and Suttle,D.P. (1997) Inhibition of DNA topoisomerase alpha gene expression by the p53 tumor suppressor. Mol. Cell. Biol., 17, 389–397.[Abstract]
Zdzienicka,M.Z. (1995) Mammalian mutants defective in the response to ionizing radiation-induced DNA damage. Mutat. Res., 336, 203–213.[Web of Science][Medline]
Zhu,J. and Schiestl,R.H. (1996) Topoisomerase I involvement in illegitimate recombination in Saccharomyces cerevisiae. Mol. Cell. Biol., 16, 1805–1812.[Abstract]
Received on December 12, 2000; accepted on April 9, 2001.
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