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Enzymatic Synthesis of CuII-responsive Deoxyribozymes through Incorporation of Artificial Ligand-type Nucleotides

中間, 貴寛東京大学 DOI:10.15083/0002004752

2022.06.22

概要

1. Introduction
　Metal-mediated base pairs, which consist of ligand-bearing nucleotides and a bridging metal ion, have gained much attention as functional units of DNA-based supramolecules and nanoarchitectures1. For example, hydroxypyridone (H) nucleotides form a 2:1 complex with a CuII ion (H–CuII– H) in a DNA duplex2 and H–CuII–H base pairing was utilized for the DNA-templated CuII assembly3 and the control of DNA conductivity4. In spite of the great potential for metal-dependent regulation of DNA functions, metal-mediated unnatural base pairs have scarcely been applied to metal-responsive DNA materials. This is mainly because chemical synthesis of artificial ligand-bearing oligonucleotides is often cumbersome and time-consuming.
　Herein, I report efficient enzymatic methods to synthesize artificial DNA strands containing H nucleotides (Figure 1). Enzymatic reactions were expected to incorporate hydroxypyridone nucleoside triphosphate (dHTP) under mild conditions without any protecting group of the ligand moiety. I subsequently applied the enzymatic synthesis to develop CuII-responsive deoxyribozymes (DNAzymes). H nucleotides were incorporated into reported DNAzymes so that the formation of one H–CuII–H base pair can regulate their catalytic activities.

2. Enzymatic synthesis of artificial ligand-bearing DNA strands
　Polymerase incorporation of dHTP was first investigated using a natural DNA template. I expected that unnatural H nucleotides can be introduced into an opposite site of natural nucleobases through misincorporation by a DNA polymerase. An exonuclease-deficient Klenow fragment (KF exo–) was found to incorporate one dHTP in a quantitative manner when the opposite base (X) was A or T.
　Next, the subsequent primer extension with natural nucleoside triphosphates (dNTPs) was examined to obtain a fully-elongated strand (Figure 2a). However, KF exo– hardly incorporated any dNTPs presumably due to the inhibition of primer elongation by the H–X mismatch. In contrast, a lesion bypass DNA polymerase, Dpo4 incorporated dNTPs after the H to afford a full-length product in over 90% yield. The product was characterized by MALDI-TOF mass spectrometry and an exonuclease-digestion experiment. This two-step primer extension allowed for the incorporation of a single H nucleotide into any sequences to afford H-containing DNA strands.
　The incorporation of multiple H nucleotides was also accomplished using a polymerase and a ligase (Figure 2b). H nucleotides were appended to the 3′-ends of DNA strands by KF exo– and the H-bearing strands were subsequently connected through ligation by T4 DNA ligase.
In addition, I investigated the enzymatic synthesis of DNA strands containing consecutive H nucleotides. Dpo4 polymerase was found to incorporate three consecutive H nucleotides with the aid of MnII ions as a cofactor. H-oligomers (e.g. 5′-GHHHC-3′) were also enzymatically incorporated into a DNA strand by T4 DNA ligase.
　These enzymatic methods enabled the incorporation of H nucleotides at internal positions without any protecting groups by using commercially available enzymes.

3. Development of CuII-responsive split DNAzymes
　DNAzymes are catalytically active DNA molecules and applied to biosensors, logic gates, and molecular machines. Thus, regulation of DNAzyme activities by external stimuli is highly demanded for developing more sophisticated DNA-based systems.
　The first CuII-responsive DNAzyme was developed based on a split design. A known RNA-cleaving DNAzyme (E5 DNAzyme5, Figure 3a) was divided into two strands, and H nucleotides were incorporated into its stem site. The split DNAzyme was expected to restore its catalytic activity upon addition of CuII ions through the formation of a H–CuII–H base pair (Figure 3b). I prepared 11 H-bearing DNA stands by the two-step primer extension (Figure 2a) to investigate the optimal position of the H–H pair. The CuII-dependent catalytic activity of each DNAzyme was evaluated with an equimolar substrate in the absence and in the presence of one equivalent of CuII ions. As a result, the highest on/off ratio (~5) was observed with a DNAzyme containing a H–H at the third position, which is referred to as “split H-DNAzyme”.
　The RNA-cleaving activity of the split H-DNAzyme was examined with 10 equivalents of the substrate (Figure 3c). The time-course analysis clarified that the split H-DNAzyme catalytically cleaved the substrate in the presence of CuII ions at the 5.5-times higher initial rate than that under the CuII-free condition. No substrate cleavage was observed with CuII ions but without any DNAzymes, which evidenced that the DNAzyme activity itself was enhanced by CuII.
　The metal specificity of the split H-DNAzyme was examined with 11 kinds of transition metal ions. Among them, only CuII ions enhanced the activity while the other ions had no effect on the RNA-cleaving reaction.
　The reversible regulation of the DNAzyme activity was demonstrated by the addition and removal of CuII ions. The addition CuII ions in the course of the reaction immediately increased the RNA-cleaving activity. When a CuII-binding peptide (GHK) was added as a chelator, the activity was immediately diminished to almost the same level as that in the absence of CuII ions. Moreover, the two-cycle switching of the DNAzyme activity was demonstrated by the alternate addition of CuII ions and the CuII-binding peptide (Figure 3d).

4. Development of CuII-responsive single-stranded DNAzymes
Next, a CuII-responsive single-stranded DNAzyme (ss H-DNAzyme) was developed from the same E5 DNAzyme. The DNAzyme strand was synthesized by incorporating two H nucleotides into a DNA stand using the enzymatic ligation (Figure 2b). The sequence of ss H-DNAzyme was designed so as to form a catalytically inactive secondary structure in the absence of CuII ions (Figure 4a). The formation of one H–CuII–H base pair could stabilize its active form and induce the structure transformation to restore the RNA-cleaving activity.
　The CuII-dependent structure conversion was verified by fluorescent assay (Figure 4b). A fluorescent cytosine analogue, pyrrolo-C (PC)6, was introduced into a stem duplex of the inactive structure, where the PC forms a base pair with a guanine and emits weaker fluorescence. When CuII ions were added, the fluorescent intensity was significantly enhanced. This indicates the dissociation of the PC–G pair caused by the CuII-induced structure conversion to the active form.
　The RNA-cleaving activity of ss H-DNAzyme was monitored under the same condition as that of split H-DNAzyme (Figure 4c). Upon addition of one equivalent of CuII ions, the initial reaction rate was enhanced by 6.8-fold, which was comparable to the split DNAzyme. The activity of ss H-DNAzyme was also reversibly controlled by the addition and removal of CuII ions. Furthermore, I succeeded in developing other CuII-responsive DNAzymes from different types of DNAzymes but based on the same design principle. Thus, the incorporation of H nucleotides was proven to be a promising method to develop metal-responsive DNAzymes.

5. Multimetal-dependent regulation of DNAzyme activities
　Based on its high metal specificity, the split H-DNAzyme was applied to metal-dependent orthogonal regulation of DNAzyme activities using well-known HgII-mediated thymine base pairs (T–HgII–T) as well as H–CuII–H (Figure 5a). A novel HgII-responsive DNAzyme (T-DNAzyme) was developed by introducing four T–T mismatches into E5 DNAzymes and their substrates. When one equivalent of CuII ions was added, the activity of H-DNAzyme was enhanced eight-fold while T-DNAzyme showed the same activity (Fig. 5b). On the other hand, the addition of HgII ions selectively increased the activity of T-DNAzyme. In the presence of both CuII and HgII ions, both DNAzymes were activated by two- to three-fold. Furthermore, the selective deactivation of the DNAzymes was also demonstrated by the removal of CuII or HgII ions using corresponding chelating agents. In this way, the orthogonal regulation of the DNAzymes was achieved through the metal-specific formation of H–CuII–H and T–HgII–T base pairs.
　A DNAzyme that responds to two metal ions was also developed through the incorporation H nucleotides into a reported AgI-dependent RNA-cleaving DNAzyme7. In the absence of AgI ions, no substrate cleavage was observed. The addition of only AgI ions but without CuII ions yielded little cleaved substrate. The activity of the modified DNAzyme was restored only when both CuII and AgI ions were added. Therefore, it displayed an AND-gate behavior using the two metal ions as inputs, which is applicable to DNA-based logic gates, multiplexer, and computing circuits.

6. Conclusion
　In my doctorial study, I have established the enzymatic synthesis of artificial ligand-bearing DNA strands and developed CuII-responsive DNAzymes. Compared to the conventional chemical synthesis, the enzymatic methods allowed for the protection-free incorporation of hydroxypyridone (H) nucleotides without any specialized equipment. CuII-responsive DNAzymes were synthesized by the enzymatic incorporation of H nucleotides. Because CuII ions rarely interfere with natural nucleotides and selectively bind to H nucleotides, the rational designs of metal-responsive DNAzymes were accomplished. The RNA-cleaving activities of both split and single-stranded DNAzymes were reversibly regulated by the formation of one H–CuII–H base pair. Moreover, multimetal-dependent regulation of DNAzyme activities was also demonstrated. The CuII-responsive DNAzymes developed here will be utilized for the metal-triggered control of DNA-based molecular machines and logic gates.
　The facile synthesis and design concepts would be applicable to other artificial ligand-bearing nucleotides. Accordingly, this study would provide a powerful tool to develop DNA materials that respond to diverse metal ions.

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Enzymatic Synthesis of CuII-responsive Deoxyribozymes through Incorporation of Artificial Ligand-type Nucleotides

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関連論文

Sequence-Specific Recognition and Cleavage of Double-Stranded DNA by Peptide Nucleic Acid

Enhancing the stability of DNA origami nanostructures by enzymatic and chemical ligation methods

Investigating Advanced Properties of Modular DNAs as Biohybrid Catalyst and Aptamer

アルキニルヌクオチドおよび当該残基を有する人工DNAの核酸関連酵素に対する適合性評価

Development of Heme Acquisition Proteins Capturing Artificial Metal Complexes and Investigation of Their Functions

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大学

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Enzymatic Synthesis of CuII-responsive Deoxyribozymes through Incorporation of Artificial Ligand-type Nucleotides

概要

関連論文

Sequence-Specific Recognition and Cleavage of Double-Stranded DNA by Peptide Nucleic Acid

Enhancing the stability of DNA origami nanostructures by enzymatic and chemical ligation methods

Investigating Advanced Properties of Modular DNAs as Biohybrid Catalyst and Aptamer

アルキニルヌクオチドおよび当該残基を有する人工DNAの核酸関連酵素に対する適合性評価

Development of Heme Acquisition Proteins Capturing Artificial Metal Complexes and Investigation of Their Functions

参考文献