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• W2015503536 abstract "We investigated the binding of an antisense oligodeoxynucleotide to a stem-loop structure corresponding to the mini-exon sequence of the protozoan parasite Leishmania amazonensis. This oligomer was designed to anneal to the single-stranded region adjacent to the bottom of the hairpin and to fold back on itself, giving rise to a “double-hairpin” complex that involved a local triplex. This imposed the recognition, by the third strand, of a “purine” strand containing 6 interspersed pyrimidines out of 15 nucleic acid bases. The sequence of the complementary oligonucleotide was derived from the so-called pyrimidine motif; the third strand of the anti-mini-exon oligomer was parallel to the purine strand of the target. Electrophoretic mobility shift assays and footprinting studies demonstrated that such an antisense oligomer was able to bind to both the DNA and RNA versions of the Leishmania hairpin. These double hairpin complexes allowed the formation at pH 6.0 of a triple-stranded structure, despite the presence of 4 A:T*G and 2 G:C*T triplets out of 15. We investigated the binding of an antisense oligodeoxynucleotide to a stem-loop structure corresponding to the mini-exon sequence of the protozoan parasite Leishmania amazonensis. This oligomer was designed to anneal to the single-stranded region adjacent to the bottom of the hairpin and to fold back on itself, giving rise to a “double-hairpin” complex that involved a local triplex. This imposed the recognition, by the third strand, of a “purine” strand containing 6 interspersed pyrimidines out of 15 nucleic acid bases. The sequence of the complementary oligonucleotide was derived from the so-called pyrimidine motif; the third strand of the anti-mini-exon oligomer was parallel to the purine strand of the target. Electrophoretic mobility shift assays and footprinting studies demonstrated that such an antisense oligomer was able to bind to both the DNA and RNA versions of the Leishmania hairpin. These double hairpin complexes allowed the formation at pH 6.0 of a triple-stranded structure, despite the presence of 4 A:T*G and 2 G:C*T triplets out of 15. The common feature of messenger RNAs from trypanosomatids is the presence at their 5′ end of a short sequence named “mini-exon” acquired during maturation of premessenger RNAs through a trans-splicing mechanism (1Borst P. Annu. Rev. Biochem. 1986; 55: 701-732Google Scholar). This mini-exon motif, which is absolutely required for translation, is therefore a very attractive target for the design of antisense oligonucleotides as anti-parasitic agents (2Hélène C. Toulmé J.J. Biochim. Biophys. Acta. 1990; 1049: 99-125Google Scholar). Potentially, a single complementary sequence will prevent the synthesis of all parasitic proteins. Indeed, oligonucleotides targeted to the mini-exon sequence of Trypanosoma brucei (3Cornelissen A.W.C.A. Verspieren P. Toulmé J.J. Swinkels B.W. Borst P. Nucleic Acids Res. 1986; 14: 5605-5614Google Scholar, 4Walder J.A. Eder P.S. Engman D.M. Brentano S.T. Walder R.Y. Knutzon D.S. Dorfman D.M. Donelson J.E. Science. 1986; 233: 569-571Google Scholar) or of Leishmania amazonensis (5Pascolo E. Blonski C. Shire D. Toulmé J.-J. Biochimie. 1993; 75: 43-47Google Scholar) were shown to inhibit in vitro translation in cell-free extracts. Moreover, an acridine-linked 9-mer, complementary to the 5′ end of T. brucei mRNAs specifically killed cultured procyclic forms of this parasite in vitro (6Verspieren P. Cornelissen A.W.C.A. Thuong N.T. Hélène C. Toulmé J.J. Gene (Amst.). 1987; 61: 307-315Google Scholar). More recently, it was reported that an anti-mini-exon phosphorothioate 16-mer, either free or associated to low density lipoproteins, displayed leishmanicidal properties against amastigotes of L. amazonensis grown in murine macrophages (7Ramazeilles C. Mishra R.K. Moreau S. Pascolo E. Toulmé J.-J. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7859-7863Google Scholar, 8Mishra R.K. Moreau C. Ramazeilles C. Moreau S. Bonnet J. Toulmé J.J. Biochim. Biophys. Acta. 1995; 1264: 229-237Google Scholar). It was previously shown that the mini-exon sequence of L. amazonensis could fold into a hairpin secondary structure (9Verspieren P. Loreau N. Thuong N.T. Shire D. Toulmé J.J. Nucleic Acids Res. 1990; 18: 4711-4717Google Scholar), which weakened the binding of antisense oligonucleotides (10Pascolo E. Hudrisier D. Sproat B. Thuong N.T. Toulmé J.-J. Biochim. Biophys. Acta. 1994; 1219: 98-106Google Scholar). Rather than competing with the intramolecular hairpin, we considered the possibility to bind an oligomer to the folded structure. This can be achieved in different ways: (i) binding to the stem via a triple-stranded structure (11Baumann U. Frank R. Blöcker H. Biochem. Biophys. Res. Commun. 1988; 157: 986-991Google Scholar) or to the loop, leading to half pseudoknot structure (12Ecker D.J. Vickers T.A. Bruice T.W. Freier S.M. Jenison R.D. Manoharan M. Zounes M. Science. 1993; 257: 958-961Google Scholar), (ii) using an oligonucleotide that bridges the single-stranded parts, upstream and downstream of the stem (13Richardson P.L. Schepartz A. J. Am. Chem. Soc. 1991; 113: 5109-5111Google Scholar, 14Cload S.T. Schepartz A. J. Am. Chem. Soc. 1991; 113: 6324-6326Google Scholar), or (iii) selecting oligomers from a random population that recognize the folded target (15Cload S.T. Schepartz A. J. Am. Chem. Soc. 1994; 116: 437-442Google Scholar, 16Mishra R.K. Toulmé J.J. C. R. Acad. Sci. Paris Life Sci. 1994; 317: 977-982Google Scholar, 17Mishra R.K. Le Tinévez R. Toulmé J.J. Proc. Natl. Acad. Sci. U. S. A. 1996; (in press)Google Scholar). The resulting complexes might actually stabilize the hairpin and interfere with mRNA translation. Alternatively, we previously described a strategy that allows accommodation of a stem-loop structure into a so-called “double hairpin” complex (18Brossalina E. Toulmé J.J. J. Am. Chem. Soc. 1993; 115: 796-797Google Scholar, 19Brossalina E. Pascolo E. Toulmé J.J. Nucleic Acids Res. 1993; 21: 5616-5622Google Scholar). The antisense oligonucleotide forms a short Watson-Crick duplex with a single-stranded sequence at the bottom of the hairpin and then folds back to give rise to a triple-stranded structure with both this short duplex and the stem of the hairpin. This approach was demonstrated using a model stem-loop purposefully designed to promote a triple helical structure; an antisense oligopyrimidine was targeted to a hairpin made exclusively of purines on the 5′ side and consequently of pyrimidines on the 3′ side, thus leading to the formation of canonical T:A*T and C:G*C+ triplets (where the colon denotes Watson-Crick base pairing and the asterisk denotes Hoogsteen hydrogen bonding with the third strand). The resulting complex involved 16-base triplets in which the two pyrimidine strands were connected by a (T)4 loop. The formation of triple helices is restricted to homopurine homopyridine sequences (2Hélène C. Toulmé J.J. Biochim. Biophys. Acta. 1990; 1049: 99-125Google Scholar). Unfortunately, nucleic acid bases are not appropriately distributed for triplex formation in the hairpin derived from the L. amazonensis mini-exon. Therefore we had to design an oligonucleotide that aimed at forming a double hairpin complex involving a triple-stranded structure with a target sequence comprising all four bases. In particular two Cs of two G-C pairs should be read by the third strand. We demonstrated that an antisense oligomer composed of the four bases was able to bind to either a DNA or a RNA folded hairpin corresponding to the L. amazonensis mini-exon sequence through the formation of G:C*T and A:T(U)*G triplets, in addition to the canonical ones. The oligonucleotides used throughout this study (see sequences in Fig. 1) were prepared “trityl on” using conventional phosphoramidite chemistry. They were purified in one step by reverse phase high pressure liquid chromatography; an acetonitrile gradient in a 100 mM triethylammonium acetate buffer (pH 7.0) was used for elution. Purity was evaluated by electrophoresis of radiolabeled oligonucleotides on a 20% polyacrylamide gel containing 7 M urea, using [γ-32P]ATP (37.5 MBq/mmol from DuPont NEN). The oligoribonucleotide 35rLa was prepared by in vitro transcription with T7 RNA polymerase as described previously (20Milligan J.F. Groebe D.R. Witherell G.W. Uhlenbeck O.C. Nucleic Acids Res. 1987; 15: 8783-8798Google Scholar). Radiolabeled mini-exon oligonucleotide 35La or 35rLa (0.1 μM) was incubated with a complementary oligonucleotide (2 μM) for 24 h at 4°C in a 50 mM sodium acetate (pH 6.0), containing 10 mM magnesium acetate. The samples were then mixed (v/v) with the dye solution (10% glycerol, 0.05% bromphenol blue, 0.05% xylene cyanol) and loaded on a 15% nondenaturing polyacrylamide gel. Overnight migration (4°C) was achieved at 0.75 mA/cm in the above buffer. Complementary oligonucleotides (0.5 μM) were incubated for 14 h at 0°C in a 50 mM sodium acetate buffer (pH 6.0) containing 30 mM magnesium acetate in a 1-cm path length quartz cuvette. The temperature was then increased at a rate of 0.5°C/min, while the UV absorption was monitored at 260 and 320 nm on a UVIKON 940 spectrophotometer. For chemical footprinting 32P 5′ end-labeled oligonucleotides were incubated for 14 h at 4°C in a 50 mM sodium acetate buffer (pH 6.0) containing 30 mM magnesium acetate, either in the absence or in the presence of the desired complementary oligonucleotide, to allow the formation of complexes prior to the addition of 22.8 mg/ml potassium permanganate. At the end of a 30-min incubation at +4°C, samples were ethanol precipitated and dissolved in 1 M piperidine (20 μl). Hydrolysis was performed by 30 min heating at 90°C. Samples were then analyzed on a 20% denaturing polyacrylamide gel. S1 mapping experiment were carried out in the enzyme buffer (50 mM sodium acetate, pH 5.7, containing 200 mM NaCl, 10 mM ZnCl2, and 5% glycerol). Oligonucleotides were incubated at 4°C for 4 h in the presence of 200 units of S1 nuclease. After precipitation by ethanol the samples were analyzed on a 20% denaturing polyacrylamide gel. Complexes formed with 35rLa RNA were characterized by digestion with Escherichia coli RNase H. After preincubating 32P-labeled 35rLa (2 nM) with a complementary oligonucleotide (1 μM) at 4°C for 24 h in a 50 mM sodium acetate buffer, 10 mM magnesium acetate, and 150 mM sodium chloride, RNase H (0.15 u/μl) was added, and the reaction was allowed for 30 min at 10°C. Samples were then analyzed on a 20% denaturing polyacrylamide gel. We studied the interaction between a 35-nucleotide-long sequence, corresponding to the mini-exon region of L. amazonensis, which can fold into a hairpin structure, and several complementary oligomers (Fig. 1). The mini-exon oligonucleotide, available either as DNA (35La) or RNA (35rLa) was used as a target for a 29-mer (29DE), whose 5′ end constituted an anchor complementary to the single-stranded part located at the bottom of the stem of the folded mini-exon, leading to a 10-base pair duplex. The sequence of the 3′ part of 29DE was chosen to optimize the formation of a triple helical structure, 15 triplets long. Although the 5′ end of 35La contained 6 pyrimidines, we considered it as the “purine strand” for the putative triple helical complex. We had to accommodate 6 purine-pyrimidine pairs, two G-Cs, and four A-Ts interspersed within pyrimidine-purine pairs. This was achieved by G reading A-T and T reading G-C, which led to the least disturbing triplets A:T*G (21Griffin L.C. Dervan P.B. Science. 1989; 245: 967-971Google Scholar, 22Mergny J.L. Sun J.S. Rougée M. Montenay-Garestier T. Barcelo F. Chomilier J. Hélène C. Biochemistry. 1991; 30: 9791-9798Google Scholar, 23Yoon K. Hobbs C.A. Koch J. Sardaro M. Kutny R. Weis A.L. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 3840-3844Google Scholar, 24Best G.C. Dervan P.B. J. Am. Chem. Soc. 1995; 117: 1187-1193Google Scholar) and G:C*T (22Mergny J.L. Sun J.S. Rougée M. Montenay-Garestier T. Barcelo F. Chomilier J. Hélène C. Biochemistry. 1991; 30: 9791-9798Google Scholar, 23Yoon K. Hobbs C.A. Koch J. Sardaro M. Kutny R. Weis A.L. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 3840-3844Google Scholar, 24Best G.C. Dervan P.B. J. Am. Chem. Soc. 1995; 117: 1187-1193Google Scholar) for purine-pyrimidine inversions in DNA triple strands. This design resulted in parallel orientations of the target purine strand and of the hypothetical third strand of the anti-mini-exon sequence. We also synthesized a control 29-mer (29Cont) with the same 10-nucleotide anchor as 29DE in the 5′ part but a different 3′ sequence, which was chosen to minimize the number of canonical triplets (Fig. 1). We first investigated the binding of oligonucleotides to the 35-mer 35La corresponding to the DNA version of the L. amazonensis mini-exon sequence using electrophoretic mobility shift assay. As previously reported (9Verspieren P. Loreau N. Thuong N.T. Shire D. Toulmé J.J. Nucleic Acids Res. 1990; 18: 4711-4717Google Scholar), this oligomer migrates as two bands on a nondenaturing polyacrylamide gel, corresponding to the minor linear form and to the major folded form (Fig. 2a). Upon the addition of the oligonucleotide 29DE, a band of intermediate mobility appears to the expense of the two bands characteristic of 35La. This revealed the formation of a 35La-29DE complex. Neither the oligonucleotides 10Cont, nor 29Cont, which can form 10 base pairs with 35La, gave rise to such a distinct retarded band; no modification of the electrophoretic profile was seen in the presence of 10Cont (not shown), whereas a smear was observed with 29Cont, indicating a weaker association than that of 29DE. Therefore, the binding of the latter oligonucleotide to the target hairpin involves more than 10 Watson-Crick base pairs, suggesting a contribution of the 3′ part of 29DE to the interaction between the two oligomers. As previously reported (9Verspieren P. Loreau N. Thuong N.T. Shire D. Toulmé J.J. Nucleic Acids Res. 1990; 18: 4711-4717Google Scholar), the UV-monitored melting of 35La displayed a cooperative transition related to the unfolding of the hairpin characterized by a Tm value of 48°C under our experimental conditions (see “Materials and Methods”). The addition of a stoechiometric amount of 29DE led to a broad transition, indicative of a loose complex with poorly cooperative interactions (not shown). A similar melting curve was obtained with the control 29-mer. Therefore Tm measurement did not allow to discriminate between the two types of complexes, 35La-29DE and 35La-29Cont. We investigated the structure of the 35La-29DE complex with chemical (KMnO4) or enzymatic probes (S1 nuclease). The complex was labeled either on the target (35La) or on the anti-mini-exon strand (29DE). Footprinting performed with potassium permanganate showed a high reactivity of thymines 9-15 of 29DE in the complex, compared with 29DE alone (Fig. 3a). In contrast, T residues from positions 18-26 were significantly less susceptible to modification. This indicates that the 3′ part of the oligonucleotide 29DE is protected through interaction with the target, whereas the T stretch is highly accessible. This might correspond to a loop structure, as confirmed by S1 mapping. Whereas this nuclease specific for single-stranded nucleic acids gave an all or nothing pattern of cleavage for 29DE alone, this oligonucleotide was specifically cleaved in the region corresponding to nucleotides 12-15 in the presence of 35La, i.e. in the T stretch that was highly reactive to KMnO4 (Fig. 3b). A similar experiment performed with the oligomer 29Cont did not show such a pattern; however, a slightly increased sensitivity of residues located 3′ to the anchor region was observed, indicative of a weak 35La-29Cont complex, in agreement with melting experiments (Fig. 3c). Drastic changes of the KMnO4 reactivity pattern were also observed for 35La upon addition of 29DE (Fig. 4). A reduced sensitivity of the T residues was generally observed in the anchor region; whereas TVI and TVIII were fully protected, TX was still available for the reaction. This latter residue faced the 5′-terminal nucleotide of the anti-mini-exon oligomer 29DE. This means that the 10-base pair duplex was actually formed in the 35La-29DE complex, but despite potential cooperative interaction between the stem structure of 35La and the double-stranded anchor site, the junction was prone to transient opening. The reactivity pattern of T residues located in the stem of 35La was also informative; TXIV was protected, whereas the sensitivity of TXVI was exacerbated (Fig. 4). Assuming that the 3′ part of 29DE constitutes the third strand of a triple-stranded complex, TXVI could be next to the triple strand-double strand junction. A previous study (18Brossalina E. Toulmé J.J. J. Am. Chem. Soc. 1993; 115: 796-797Google Scholar) performed with a model sequence, designed to generate a double hairpin complex, has shown hyper-reactivity of the G residue located at the duplex-triplex junction, indicative of a distorted structure. A similar effect was also described for a linear triplex made from three independent strands (25François J.F. Saison-Behmoaras T. Hélène C. Nucleic Acids Res. 1988; 16: 11431-11440Google Scholar, 26Chomilier J. Sun J.S. Collier D.A. Garestier T. Hélène C. Lavery R. Biophys. Chem. 1992; 45: 143-152Google Scholar). In the present case the junction coinciding with a bulge might potentiate the conformation change. An additional effect could also contribute as discussed below for 10Cont. The oligomer 10Cont, able to form a perfect duplex in the anchor region of 35La, yielded a different pattern of cleavage. As expected, this oligonucleotide protected TVI and TVIII, (slightly less than 29DE), whereas TX pairing with the 5′-terminal A of 10Cont was still reactive (Fig. 4). But TXIV, located in the stem remained accessible, in contrast to what was observed in the presence of 29DE. Surprisingly, TXVI was more reactive in the presence than in the absence of 10Cont, although it is located 6nt away from the 5′ end of the anti-mini-exon oligomer (Fig. 4). This might suggest a conformation change of the target hairpin upon hybridization of the 10-mer, as observed for other complexes involving stem-loop structures (53Brossalina E. Demchenko E. Demchenko Y. Vlassov V. Toulmé J.J. Nucleic Acids Res. 1996; (in press)Google Scholar). S1 mapping of the target also revealed conformational changes upon binding of 29DE. In the absence of any added oligomer, 35La was cleaved by S1 nuclease at TXX, i.e. in the loop, and at TXXVI, which faces the bulge (Fig. 5). Both sites were protected in the presence of 29DE. Interestingly, the addition of 10Cont, which enhanced the reactivity of the bulged T to KMnO4, did not change the S1 sensitivity of the opposite strand at TXXVI. Neither was any change seen at TXX (Fig. 5). Therefore, 35La-29DE complex involves definitely more than the formation of 10 base pairs in the anchor domain. From the footprinting assays whose results are summarized in Scheme 1, it can be described as a double hairpin structure similar to the one reported previously for a model sequence (18Brossalina E. Toulmé J.J. J. Am. Chem. Soc. 1993; 115: 796-797Google Scholar); the 5′ end of 29DE is paired with the single-stranded region of 35La located at the bottom of the stem, whereas the 3′ moiety of the anti-mini-exon sequence forms the third strand of a triple-stranded structure, the T residues 11-14 being a connecting loop. Because in the antisense strategy RNA is the physiological target of complementary oligonucleotides, it was of interest to monitor the binding of 29DE to 35rLa, an RNA hairpin homologous to the 35La DNA. We first studied the formation of 35rLa-29DE complex by band shift assay on a nondenaturing polyacrylamide gel. The RNA hairpin migrates as two bands, the most prominent one corresponding to the folded form. The oligonucleotide 29DE induced the appearance of two bands, the major one moving between those corresponding to the linear and the folded forms of 35rLa (Fig. 2b). A weak band also appeared above the one corresponding to the linear 35rLa, suggesting the formation of a second type of complex that was not detected with the DNA target. No retarded bands were observed with either 10Cont or 29Cont (not shown). Therefore, as for the DNA target, the interaction between 35rLa and 29DE extends beyond a 10-base pair duplex formed by the 5′ end of 29DE and the complementary region of 35rLa. Ribonuclease H is able to cleave an RNA strand hybridized to a complementary DNA strand, but it is unable to digest RNA involved in a canonical pyrimidine-purine.primidine triple-stranded structure (27Crouch R.J. New Biol. 1990; 2: 771-777Google Scholar, 28Toulmé J.J. Tidd D. Crouch H.R.J. Toulmé J.J. Ribonucleases. John Libbey, Paris1996Google Scholar). 1R. Le Tinévez and J.-J. Toulmé, unpublished observations. We used E. coli RNase H to probe the complexes formed by 35rLa with either 10Cont or 29DE. The 10-mer, which forms a regular double-stranded heteroduplex, induced the cleavage of the RNA hairpin from Cv to Tx, with a marked preferential triad, AVII/TVIII/AIX, at pH 6.0 as well as at pH 7.3 (Fig. 6). In contrast, these cleavage sites were no longer detected in the presence of 29DE at pH 6.0 (Fig. 6b), indicating that the 3′ part of 29DE protected partially 35rLa from RNase H activity. This was likely related to the formation of a triple-stranded structure as raising the pH up to 7.3, conditions which are known to distabilize C:G*C+ triplets, restored the cleavage pattern characteristic of the 35rLa-10Cont double-strand (Fig. 6b). However, three unexpected cleavage sites were observed at pH 6.0 for the 35rLa-29DE complex, the two prominent ones being at CIII and CV (Fig. 6a). Assuming the likely formation of a triple-stranded complex under these conditions, these positions correspond to G:C*T triplets. In DNA triple helices these triplets are known to have a low stability (22Mergny J.L. Sun J.S. Rougée M. Montenay-Garestier T. Barcelo F. Chomilier J. Hélène C. Biochemistry. 1991; 30: 9791-9798Google Scholar, 23Yoon K. Hobbs C.A. Koch J. Sardaro M. Kutny R. Weis A.L. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 3840-3844Google Scholar, 24Best G.C. Dervan P.B. J. Am. Chem. Soc. 1995; 117: 1187-1193Google Scholar). It is tempting to speculate that the noncanonical dG:rC*dT triplets adopt a partly open or a distorded structure that is detected by the enzyme. But, very likely the enzyme does not locally displace the third strand because this would have led to a cleavage pattern of the anchor binding site similar to that observed with the 10-mer 10Cont. Therefore, RNase H proved to be a very sensitive probe because the E. coli enzyme was able to recognize a single deoxyribo-ribo (D-R) pair (namely G-C “mismatched” with T) in a nonsubstrate surrounding, i.e. triple-stranded structures. Interestingly, human and bovine RNases HI have been shown to cleave in the vicinity of a single R-D pair comprised in double-stranded DNA (29Huang L. Kim Y. Turchi J.J. Bambara R.A. J. Biol. Chem. 1994; 269: 25922-25927Google Scholar, 30Eder P.S. Walder J.A. J. Biol. Chem. 1991; 266: 6472-6479Google Scholar). Moreover, as the experiments were performed at 10°C, it means that the nonperfect triplex was stable under these conditions or that the enzyme stabilized it. In any case, RNase H was still able to bind to the complex, despite the presence of the third strand in the major groove. This indicates that the enzyme interacts in the minor groove of the heteroduplex, as usually observed for proteins that do not display sequence specificity. Triple helix formation can be achieved in two different modes termed the pyrimidine motif and the purine motif, depending on the third strand (31Thuong N.T. Hélène C. Angew. Chem. Int. Ed. Engl. 1993; 32: 666-690Google Scholar). Both are restricted to the recognition of duplexes made of purine in one strand and pyrimidine in the second one, leading to the formation of C:G*C+ and T:A*T triplets for the pyrimidine motif, of C:G*G and T:A*A (or T:A*T) triplets for the purine one. Up to now it was not possible to recognize every double-stranded sequence even though the use of modified nucleic acid bases (32Koh J.S. Dervan P.B. J. Am. Chem. Soc. 1992; 114: 1470-1478Google Scholar, 33Wagner R.W. Matteucci M.D. Lewis J.G. Gutierrez A.J. Moulds C. Froehler B.C. Science. 1993; 260: 1510-1513Google Scholar), intercalating agent-oligonucleotide conjugates (34Mergny J.L. Duval-Valentin G. Nguyen C.H. Perrouault L. Faucon B. Rougée M. Montenay-Garestier T. Bisagni E. Hélène C. Science. 1992; 256: 1681Google Scholar, 35Cassidy S.A. Strekowski L. Wilson W.D. Fox K.R. Biochemistry. 1994; 33: 15338-15347Google Scholar), triplex dimerization (36Distefano M.D. Shin J.A. Dervan P.B. J. Am. Chem. Soc. 1991; 113: 5901-5902Google Scholar) or “strand switching” (37Beal P.A. Dervan P.B. J. Am. Chem. Soc. 1992; 114: 4976-4982Google Scholar, 38Froehler B.C. Terhorst T. Shaw J.P. Mccurdy S.N. Biochemistry. 1992; 31: 1603-1609Google Scholar) extends the number of sequences that can give rise to stable triple-stranded structures." @default.
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• W2015503536 date "1996-09-01" @default.
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• W2015503536 title "Double Hairpin Complexes Allow Accommodation of All Four Base Pairs in Triple Helices Containing Both DNA and RNA Strands" @default.
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