Key points are not available for this paper at this time.
We recently showed that abasic sites, uracil mismatches, nicks, and gaps can trap DNA topoisomerase I (top1) when these lesions are introduced in the vicinity of a top1 cleavage site (Pourquier, P., Ueng, L.-M., Kohlhagen, G., Mazumder, A., Gupta, M., Kohn, K. W., and Pommier, Y. (1997) J. Biol. Chem. 272, 7792–7796; Pourquier, P., Pilon, A. A., Kohlhagen, G., Mazumder, A., Sharma, A., and Pommier, Y. (1997)J. Biol. Chem. 26441–26447). In this study, we investigated the effects on top1 of an abundant base damage generated by various oxidative stresses: 7,8-dihydro-8-oxoguanine (8-oxoG). Using purified eukaryotic top1 and oligonucleotides containing the 8-oxoG modification, we found a 3–7-fold increase in top1-mediated DNA cleavage when 8-oxoG was present at the +1 or +2 position relative to the cleavage site. Another oxidative lesion, 5-hydroxycytosine, also enhanced top1 cleavage by 2-fold when incorporated at the +1 position of the scissile strand. 8-oxoG at the +1 position enhanced noncovalent top1 DNA binding and had no detectable effect on DNA religation or on the incision step. top1 trapping by 8-oxoG was markedly enhanced when asparagine adjacent to the catalytic tyrosine was mutated to histidine, suggesting a direct interaction between this residue and the DNA major groove immediately downstream from the top1 cleavage site. Altogether, these results demonstrate that oxidative base lesions can increase top1 binding to DNA and induce top1 cleavage complexes. We recently showed that abasic sites, uracil mismatches, nicks, and gaps can trap DNA topoisomerase I (top1) when these lesions are introduced in the vicinity of a top1 cleavage site (Pourquier, P., Ueng, L.-M., Kohlhagen, G., Mazumder, A., Gupta, M., Kohn, K. W., and Pommier, Y. (1997) J. Biol. Chem. 272, 7792–7796; Pourquier, P., Pilon, A. A., Kohlhagen, G., Mazumder, A., Sharma, A., and Pommier, Y. (1997)J. Biol. Chem. 26441–26447). In this study, we investigated the effects on top1 of an abundant base damage generated by various oxidative stresses: 7,8-dihydro-8-oxoguanine (8-oxoG). Using purified eukaryotic top1 and oligonucleotides containing the 8-oxoG modification, we found a 3–7-fold increase in top1-mediated DNA cleavage when 8-oxoG was present at the +1 or +2 position relative to the cleavage site. Another oxidative lesion, 5-hydroxycytosine, also enhanced top1 cleavage by 2-fold when incorporated at the +1 position of the scissile strand. 8-oxoG at the +1 position enhanced noncovalent top1 DNA binding and had no detectable effect on DNA religation or on the incision step. top1 trapping by 8-oxoG was markedly enhanced when asparagine adjacent to the catalytic tyrosine was mutated to histidine, suggesting a direct interaction between this residue and the DNA major groove immediately downstream from the top1 cleavage site. Altogether, these results demonstrate that oxidative base lesions can increase top1 binding to DNA and induce top1 cleavage complexes. DNA is highly susceptible to reactive oxygen species in vivo, especially hydroxyl radicals that are generated by various forms of oxidative stress such as lipid peroxidation, products of inflammation, cellular respiration, and nearly ultraviolet light (1Blount B.C. Mack M.M. Wehr C.M. MacGregor J.T. Hiatt R.A. Wang G. Wickramasinghe S.N. Everson R.B. Ames B.N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3290-3295Crossref PubMed Scopus (1176) Google Scholar,2Lindahl T. Nature. 1993; 362: 709-715Crossref PubMed Scopus (4226) Google Scholar). Many oxidized bases have been identified in mammalian DNA (3Dizdaroglu M. Mutat. Res. 1992; 275: 331-342Crossref PubMed Scopus (493) Google Scholar).In vivo measurements indicate that oxidatively modified bases range from a few hundred to 4 × 105/cell/day depending on the technique used (4Roldan-Arjona T. Wei Y.-F. Carter K.C. Klungland A. Anselmino C. Wang R.-P. Augustus M. Lindahl T. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8016-8020Crossref PubMed Scopus (340) Google Scholar). Among these, 7,8-dihydro-8-oxoguanine (8-oxoG) 1The abbreviations used are:8-oxoG, 8-oxoguanine; top1, DNA topoisomerase I; 5-ohC, 5-hydroxycytosine; CPT, camptothecin.1The abbreviations used are:8-oxoG, 8-oxoguanine; top1, DNA topoisomerase I; 5-ohC, 5-hydroxycytosine; CPT, camptothecin. represents the most abundant lesion with estimates of about 100,000 8-oxoG being formed and excised on average per rat cell per day (5Park E.-M. Shigenaga M.K. Degan P. Korn T.S. Kitzler J.W. Wehr C.M. Kolachana P. Ames B.N. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 3375-3379Crossref PubMed Scopus (276) Google Scholar). A recent study comparing different techniques reported a lesser but still formidable amount of 8-oxoG produced in young rat liver with a steady-state level of 0.04 adducts/105 G (6Helbock H.J. Beckman K.B. Shigenaga M.K. Walter P.B. Woodall A.A. Yeo H.C. Ames B.N. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 288-293Crossref PubMed Scopus (612) Google Scholar). Conversion of G to 8-oxoG results in retention of three hydrogen bonds between 8-oxoG and C and hence does not severely alter DNA architecture as determined by x-ray crystallography (7Lipscomb L.A. Peek M.E. Morningstar M.L. Verghis S.M. Miller E.M. Rich A. Essigmann J.M. Williams L.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 1995: 719-723Crossref Scopus (217) Google Scholar) (see Fig. 1 B). However, polymerases involved in DNA replication selectively incorporate A opposite to 8-oxoG (8Shibutani S. Takeshita M. Grollman A.P. Nature. 1991; 349: 431-434Crossref PubMed Scopus (2016) Google Scholar). In this case, 8-oxoG adopts the syn conformation, a geometry favoring two hydrogen bonds with A (7Lipscomb L.A. Peek M.E. Morningstar M.L. Verghis S.M. Miller E.M. Rich A. Essigmann J.M. Williams L.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 1995: 719-723Crossref Scopus (217) Google Scholar, 9Kouchakdjian M. Bodepudi V. Shibutani S. Eisenberg M. Johnson F. Grollman A.P. Patel D.J. 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Pyrimidines also undergo oxidation in vivo and can lead to potential mutagenic derivatives such as 5-hydrocycytosine (5-ohC) (15Feig D.I. Sowers L.C. Loeb L.A. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 6609-6613Crossref PubMed Scopus (191) Google Scholar, 16Purmal A.A. Kow Y.W. Wallace S.S. Nucleic Acids Res. 1994; 22: 72-78Crossref PubMed Scopus (152) Google Scholar). In Escherichia coli, oxidized bases are removed by specific enzymes. 5-ohC is removed by endonuclease III and formamidopyrimidine DNA N-glycosylase also known as MutM (17Hatahet Z. Kow Y.W. Purmal A.A. Cunningham R.P. Wallace S.S. J. Biol. Chem. 1994; 269: 18814-18820Abstract Full Text PDF PubMed Google Scholar, 18Wang D. Essigmann J.M. Biochemistry. 1997; 36: 8628-8633Crossref PubMed Scopus (31) Google Scholar). MutM also removes 8-oxoG paired to a C. When 8-oxoG is paired with A, the MutY glycosylase excises the complementary strand A residue that has been misincorporated by the polymerase (13Michaels M.L. Miller J.H. J. Bacteriol. 1992; 174: 6321-6325Crossref PubMed Scopus (608) Google Scholar). It has been proposed that the abnormal DNA major groove hydrogen bonding properties of oxoG, attributable specifically to the 8-oxo carbonyl, are responsible for recognition by glutamine or asparagine residues of the glycosylases (7Lipscomb L.A. Peek M.E. Morningstar M.L. Verghis S.M. Miller E.M. Rich A. Essigmann J.M. Williams L.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 1995: 719-723Crossref Scopus (217) Google Scholar). A number of cellular enzymes from yeast, Drosophila, and humans are capable of recognizing 8-oxoG, including glycosylases and the nucleotide excision repair complex (4Roldan-Arjona T. Wei Y.-F. Carter K.C. Klungland A. Anselmino C. Wang R.-P. Augustus M. Lindahl T. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8016-8020Crossref PubMed Scopus (340) Google Scholar, 19Yacoub A. Augeri L. Kelley M.R. Doetsch P.W. Deutsch W.A. 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Cell. 1985; 41: 541-551Abstract Full Text PDF PubMed Scopus (216) Google Scholar, 25Pourquier P. Pilon A.A. Kohlhagen G. Mazumder A. Sharma A. Pommier Y. J. Biol. Chem. 1997; 272: 26441-26447Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). DNA topoisomerases play a critical role in DNA by the of DNA 1996; PubMed Scopus Google Scholar). top1 is an O. Cell. Biol. 1996; 16: PubMed Scopus Google Scholar, T. Brown 1994; 29: Scopus Google Scholar) and ubiquitous enzyme 1996; PubMed Scopus Google Scholar, M. A. Pommier Y. 1995; PubMed Scopus Google Scholar, J. Wang DNA and Scholar). It a by a between a DNA strand and an enzyme tyrosine residue for a downstream to the cleavage site J. Biol. Chem. Full Text PDF PubMed Google Scholar). cleavage are the catalytic that of DNA and top1 such as and derivatives the religation of the top1 cleavage 1994; 94: Scholar, Y. 1996; Google Scholar). DNA such as uracil mismatches, abasic sites, nicks, and can also trap top1 cleavage and in lead to the of cleavage also to as P. Pilon A.A. Kohlhagen G. Mazumder A. Sharma A. Pommier Y. J. Biol. Chem. 1997; 272: 26441-26447Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, K. Westergaard O. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar, K. Westergaard O. J. Biol. 1991; PubMed Scopus Google Scholar, P. Kohlhagen G. Mazumder A. M. Pommier Y. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar, P. Pommier Y. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). In this we for the that 8-oxoG can of top1 cleavage by top1 binding to We also demonstrate the of the residue immediately the catalytic tyrosine by using various top1 including an that was found to induce A. Kohlhagen G. Y. Pommier Y. Res. 1995; Google Scholar). the of DNA lesions top1 and on the of specific residues of eukaryotic top1 with purified and oligonucleotides from The oligonucleotides to and as D. Essigmann J.M. Biochemistry. 1997; 36: 8628-8633Crossref PubMed Scopus (31) Google Scholar, M.L. Essigmann J.M. Chem. Res. 1997; PubMed Scopus Google Scholar). was from and from was by and of at and to 1 in was using with as Y. J. Kohlhagen G. F. Mutat. Res. 1995; PubMed Scopus Google Scholar). a to DNA oligonucleotides to the of complementary strand in 1 to and to of the top1 was in using a containing the top1 1994; PubMed Scopus Google Scholar). from 4 as P. Pilon A.A. Kohlhagen G. Mazumder A. Sharma A. Pommier Y. J. Biol. 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DNA with or top1 or for at in by the was by the of for at for or at 4 for of the of 1 1 to at at for and on and using a DNA in the of of in C. Wang J. S. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google and of DNA for at of to a in was for at in and using a In this study, we investigated the effects of the abundant oxidative lesion 8-oxoG on top1 and such this we used oligonucleotides from a DNA (24Bonven B.J. Gocke E. Westergaard O. Cell. 1985; 41: 541-551Abstract Full Text PDF PubMed Scopus (216) Google Scholar) containing a top1 cleavage site that had been mutated to top1 to and derivatives P. Pilon A.A. Kohlhagen G. Mazumder A. Sharma A. Pommier Y. J. Biol. Chem. 1997; 272: 26441-26447Abstract Full Text Full Text PDF PubMed Scopus (157) Google A. Kohlhagen G. F. Pommier Y. Biochemistry. 1995; Scopus Google Scholar) 1 We the effect of 8-oxoG incorporation at the +1 position of the scissile strand in Fig. 1 on top1-mediated cleavage using purified of G by 8-oxoG at the +1 position enhanced cleavage and The increase was when 8-oxoG was paired with A as be polymerase misincorporation and 8-oxoG at the +1 position of the strand in Fig. 1 not top1-mediated DNA cleavage 1 results are with that DNA at this +1 position can trap top1 and increase DNA cleavage P. Kohlhagen G. Mazumder A. M. Pommier Y. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, P. Pommier Y. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). top1 cleavage is to religation of the DNA strand. The top1 can be religation by the A. Kohlhagen G. F. Pommier Y. Biochemistry. 1995; Scopus Google Scholar). In the of the top1 cleavage the of 1 results when 5-ohC was used as a modified When introduced at the +1 position of the scissile 5-ohC enhanced top1 cleavage 2-fold However, 5-ohC to top1 when was incorporated at the +1 the position of the strand opposite to G to the and the of the oxidized +1 base on the scissile strand the of the DNA major groove and Fig. these results indicate that of an oxygen in the DNA major groove on the +1 base of the scissile strand selectively the of top1 cleavage complexes. we that top1 cleavage by with the +1 of the top1 cleavage site Y. Kohlhagen G. F. F. M.E. Proc. Natl. Acad. Sci. U. S. A. 1995; PubMed Scopus Google we the 8-oxoG and 5-ohC at the +1 position the of Fig. 1 C that the 8-oxoG had no effect on top1 to when 8-oxoG was paired to C was also and However, when 8-oxoG was paired to A, was not to top1 cleavage and also the of effect of 5-ohC on results demonstrate the of and to trap top1 when present to the top1 cleavage site on the scissile strand We the of the position of the 8-oxoG by the present in the vicinity of the top1 site 8-oxoG at the +2 position on the scissile strand also to top1 trapping and top1 cleavage was to the as for the 8-oxoG at the +1 position incorporation of 5-ohC at the +2 position of the strand not increase the of top1 cleavage When the at the position of the strand was by 8-oxoG, cleavage at the site detectable B). However, a cleavage site was two bases is with that the of abasic or of a at the position of the strand this top1 cleavage to the cleavage site P. Pilon A.A. Kohlhagen G. Mazumder A. Sharma A. Pommier Y. J. Biol. Chem. 1997; 272: 26441-26447Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, P. Kohlhagen G. Mazumder A. M. Pommier Y. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). It is to that the 8-oxoG was incorporated at position relative to the cleavage site. We also the effect of this 8-oxoG incorporation at the position of the strand on cleavage on the strand and not cleavage of this strand not at the top1 cleavage site in the with 8-oxoG at +2 and and and cleavage was and However, not increase top1-mediated cleavage at the site and We have the of when an abasic site was present at the position P. Kohlhagen G. Mazumder A. M. Pommier Y. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). results demonstrate that 8-oxoG can top1 cleavage when present at the +1 or +2 position relative to a top1 site and that can induce top1 the by 8-oxoG enhanced top1 we with the in Fig. was enhanced in the 8-oxoG 1 and a at about the cleavage level in the top1-mediated DNA religation was at of 4 B). these religation is at and in the of A. Kohlhagen G. F. Pommier Y. Biochemistry. 1995; Scopus Google Scholar). a we used the in the of CPT, of top1 cleavage by is known to from of religation of top1 cleavage A. Kohlhagen G. F. Pommier Y. Biochemistry. 1995; Scopus Google Scholar). cleavage was in the of 8-oxoG 1 cleavage detectable for 1 When with the in the absence of CPT, religation as of the cleavage not 8-oxoG at the +1 position does not to the effect of CPT, top1-mediated DNA the effects of 8-oxoG on the of DNA cleavage by top1, we used a also to as containing the 8-oxoG at the +1 position relative to the top1 cleavage site top1 to the DNA a K. Westergaard O. J. Biol. 1991; PubMed Scopus Google Scholar, S. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar). The strand was at to religation Y. J. Kohlhagen G. F. Mutat. Res. 1995; PubMed Scopus Google Scholar, S. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar). using this cleavage can be S. Biochemistry. 1997; 36: PubMed Scopus Google Scholar). Fig. that the of 8-oxoG at the +1 position not increase top1 cleavage as with the in the of the that the increase in top1 cleavage at as in Fig.1 was not to an of DNA We investigated the effect of 8-oxoG on the of noncovalent using a top1 the catalytic tyrosine was mutated to the incision but is still to the top1 J. Biol. Chem. Full Text PDF PubMed Google Scholar, Wang Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). C. A. and J. Biol. Chem. Using we found that of produced an increase in noncovalent binding was with the containing 8-oxoG G at the +1 position A, between the and the of the about a increase with the of enzyme A, and about with the A, of 5-ohC at the +1 position of the not DNA binding the B). of top1 cleavage by incorporation of 8-oxoG to enhanced binding of top1 to the in species but highly especially in the vicinity of the catalytic tyrosine in the M. A. Pommier Y. 1995; PubMed Scopus Google Scholar) We investigated the of the asparagine immediately the catalytic tyrosine for the of top1 cleavage complex by this we used three different top1 asparagine was mutated to histidine, or of the purified was with the and with oligonucleotides containing an 8-oxoG at the +1 or the +2 position B). top1 and the asparagine to cleavage with the at +1 In when asparagine was mutated to or histidine, top1 cleavage enhanced the of DNA cleavage was of 8-oxoG at the +1 or +2 to a increase in top1-mediated cleavage for top1, using the enzyme of cleavage was also when the asparagine was mutated to or When 8-oxoG was incorporated at the +2 position of the scissile the to of DNA cleavage increase as with the of the asparagine immediately adjacent to the catalytic tyrosine of top1 by DNA cleavage in study for the that 8-oxoG, is of the most abundant oxidative DNA lesions in mammalian (5Park E.-M. Shigenaga M.K. Degan P. Korn T.S. Kitzler J.W. Wehr C.M. Kolachana P. Ames B.N. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 3375-3379Crossref PubMed Scopus (276) Google can induce the of DNA In an increase of top1-mediated cleavage results from a in the the present study, enhanced top1 cleavage by DNA mismatches, abasic sites, or P. Kohlhagen G. Mazumder A. M. Pommier Y. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google and P. Pommier Y. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) was found to from of as in the of J. Wang DNA and Scholar, 1994; 94: Y. 1993; PubMed Scopus Google Scholar). in this study we found that 8-oxoG paired with C at the +1 position enhanced top1 cleavage by the binding of top1 to We also found that oxidation of +1 on the scissile strand oxidative damage found to be mutagenic in D.I. Sowers L.C. Loeb L.A. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 6609-6613Crossref PubMed Scopus (191) Google and Essigmann J.M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: PubMed Scopus Google Scholar) enhanced top1-mediated DNA effect on top1 is specific we not in cleavage or binding when or incorporated at the +1 position on the strand. of G by 8-oxoG in DNA does not base or DNA (7Lipscomb L.A. Peek M.E. Morningstar M.L. Verghis S.M. Miller E.M. Rich A. Essigmann J.M. Williams L.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 1995: 719-723Crossref Scopus (217) Google top1 binding is to the of the 8-oxo in the vicinity of the strand in the DNA major in Fig. 1 oxidation of G the position from hydrogen to and the position from a hydrogen to a hydrogen (7Lipscomb L.A. Peek M.E. Morningstar M.L. Verghis S.M. Miller E.M. Rich A. Essigmann J.M. Williams L.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 1995: 719-723Crossref Scopus (217) Google Scholar). the DNA major groove are for recognition by DNA repair enzymes such as the DNA MutM (7Lipscomb L.A. Peek M.E. Morningstar M.L. Verghis S.M. Miller E.M. Rich A. Essigmann J.M. Williams L.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 1995: 719-723Crossref Scopus (217) Google Scholar). the of 5-ohC and the 8-oxo of 8-oxoG are the position in the DNA major groove and top1 cleavage is that by the We that the of hydrogen the major groove top1 binding to 8-oxoG or on the recently of a complex L. M.R. 1998; PubMed Scopus (608) Google Scholar, M.R. L. P. 1998; PubMed Scopus Google asparagine in top1 the in Fig. is a hydrogen for the of is in with the +1 base on the scissile strand M.R. L. P. 1998; PubMed Scopus Google Scholar). asparagine to a potential interaction with 8-oxoG the the to the be to the of It is also that the asparagine to the of the adjacent catalytic A in vivo DNA is the incorporation of an A opposite 8-oxoG by DNA lesion is top1-mediated DNA cleavage was enhanced when 8-oxoG was paired to A at the +1 base is in an in the of the 8-oxo in the of the DNA and hydrogen bonding L.A. Peek M.E. Morningstar M.L. Verghis S.M. Miller E.M. Rich A. Essigmann J.M. Williams L.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 1995: 719-723Crossref Scopus (217) Google and Fig. 1 B). base was to top1-mediated religation in the absence of CPT, could not not We reported that DNA at the +1 position of a top1 cleavage site top1-mediated cleavage P. Kohlhagen G. Mazumder A. M. Pommier Y. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar). in the of the we that DNA and of religation to top1 has been to with the +1 base immediately downstream of the top1 cleavage site Y. Kohlhagen G. F. F. M.E. Proc. Natl. Acad. Sci. U. S. A. 1995; PubMed Scopus Google Scholar). interaction has been to DNA religation by top1 and to trap the top1 cleavage complexes. We found that when 8-oxoG was paired with C at the +1 However, the was markedly when 8-oxoG was paired to A at this We reported such a of in the of or abasic at this +1 base such as that of not P. Kohlhagen G. Mazumder A. M. Pommier Y. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). results the of base at the +1 position for results are also with the interaction of at the with the +1 base It is also that the top1 trapping effect of 8-oxoG was with from not that top1 can the 8-oxoG in the of other and can for of top1 cleavage by oxidized bases could lead to DNA damage and cell in the of or to and mutagenic The potential role that specific DNA repair play in the processing of these lesions has to be We and for and the of these
Pourquier et al. (Mon,) studied this question.
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