Induced‐Fit Recognition of CCG Trinucleotide Repeats by a Nickel–Chromomycin Complex Resulting in Large‐Scale DNA Deformation

Tseng, Wen-Hsuan; Chang, Chung-ke; Wu, Pei-Ching; Hu, Nien-Jen; Lee, Gene‐Hsiang; Tzeng, Ching‐Cherng; Neidle, Stephen; Hou, Ming-Hon

doi:10.1002/ange.201703989

Cited by 3 publications

(3 citation statements)

References 36 publications

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“…Some water molecules not observed in the NMR structure were also found to form hydrogen bonds with the guanine O6 and N1 atoms, which may further stabilize the overall structure ( Fig. 3 D and E) (14). These interactions at the stem may all assist in stabilizing the hairpin structure.…”

Section: Significancementioning

confidence: 97%

Parity-dependent hairpin configurations of repetitive DNA sequence promote slippage associated with DNA expansion

Huang

Chang

Kao

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Repetitive DNA sequences are ubiquitous in life, and changes in the number of repeats often have various physiological and pathological implications. DNA repeats are capable of interchanging between different noncanonical and canonical conformations in a dynamic fashion, causing configurational slippage that often leads to repeat expansion associated with neurological diseases. In this report, we used single-molecule spectroscopy together with biophysical analyses to demonstrate the parity-dependent hairpin structural polymorphism of TGGAA repeat DNA. We found that the DNA adopted two configurations depending on the repeat number parity (even or odd). Transitions between these two configurations were also observed for longer repeats. In addition, the ability to modulate this transition was found to be enhanced by divalent ions. Based on the atomic structure, we propose a local seeding model where the kinked GGA motifs in the stem region of TGGAA repeat DNA act as hot spots to facilitate the transition between the two configurations, which may give rise to disease-associated repeat expansion.DNA tandem repeats | DNA slippage | single-molecule spectroscopy | X-ray crystallography D NA replication is a crucial process in all living organisms. Mishaps in the replication process generally lead to deleterious consequences but also drive biological evolution (1). Changes in the number of tandem copies of a specific DNA sequence within the genome are associated with devastating neuropathies and various types of cancer (2, 3). On the other hand, these changes also help shape normal genomic features such as microsatellite polymorphism, which are often used as markers for population biology studies (4).The unit sizes of repetitive DNA sequences involved in repeat number changes range from a single base (e.g., microsatellites) to dodecanucleotides (12 bases, e.g., in progressive myoclonic epilepsy type 1) (5, 6). DNA slippage is believed to be a primary mechanism driving the change in repeat number of various unit sizes. Repetitive DNA sequences often form alternative structures such as bulges and hairpin loops in addition to canonical DNA conformations (7,8). A repeat unit may slip between being part of a hairpin loop, a bulge, or a duplex in a dynamic fashion, which may alter the course of normal cellular DNA chemistry and ultimately lead to repeat expansion associated with neurological diseases (9). (TGGAA) n repeats, for example, may form noncanonical structures such as a hairpin arm (10, 11) or an antiparallel duplex (12). Expansion of this pentanucleotide sequence has been associated with spinocerebellar ataxia 31 (SCA31), an adult-onset autosomal-dominant neurodegenerative disorder (13).In this article, we probed the conformational heterogeneity and stability of hairpins composed of repetitive TGGAA sequences using single-molecule fluorescence resonance energy transfer [single-molecule FRET (smFRET)] spectroscopy and X-ray crystallography as primary tools. Remarkably, we were able to detect two distinct hairpin confi...

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Section: Significancementioning

confidence: 97%

Parity-dependent hairpin configurations of repetitive DNA sequence promote slippage associated with DNA expansion

Huang

Chang

Kao

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…12 These unusual structures, originating from base-pair mismatch and repetitive sequence motifs, usually carry unique structural features that can be recognized by small-molecule ligands for potential disease detection or therapeutic applications. 13,14 Among these TNR sequences, CTG/CAG is responsible for the most (over 14) types of neurodegenerative disorders, for example, Huntington's disease, myotonic dystrophy, and spinocerebellar ataxia (SCA). 15,16 Single-stranded CTG and CAG repeats fold into thermodynamically stable stem-loop hairpins.…”

mentioning

confidence: 99%

Long-Range Hairpin Slippage Reconfiguration Dynamics in Trinucleotide Repeat Sequences

Wei

Shen

et al. 2019

J. Phys. Chem. Lett.

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Trinucleotide repeat (TNR) sequences, which are responsible for several neurodegenerative genetic diseases, fold into hairpins that interfere with the protein machinery in replication or repair, thus leading to dynamic mutation -abnormal expansions of the genome. Despite their high thermodynamic stability, these hairpins can undergo configurational rearrangements, which may be crucial for continuous dynamic mutation. Here, we used CTG repeats as a model system to study their structural dynamics at the single-molecule level. A unique dynamic two-state configuration interchange was discovered over a wide range of odd-numbered CTG repeat sequences. Employing repeat-number-dependent kinetic analysis, we proposed a bulge translocation model, which is driven by the local instability and can be extended reasonably to longer (pathologically relevant) hairpins, implying the potential role in error accumulation in repeat expansion.

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“…Numerous studies have shown that many small-molecule intercalators with pharmaceutical and/or diagnostic potential ( Satange et al, 2018 ; Pages et al, 2019 ) can recognize mismatched DNA or RNA duplexes and induce various degrees of structural deformations. The existence of unstable mismatches in nucleic acid sequences may cause nucleobases flipping into additional helical positions, which itself is a significant phenomenon observed during the binding of small-molecule ligands to DNA or RNA duplexes ( Jourdan et al, 2012 ; Tseng et al, 2017 ). DNA bending is also considered to be an important consequence of the action of those small molecules inserted into the DNA duplexes ( Hou et al, 2002 ; Hall et al, 2011 ; Hall et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

The Research of G–Motif Construction and Chirality in Deoxyguanosine Monophosphate Nucleotide Complexes

Zhu

Wang

et al. 2021

Front. Chem.

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A detailed understanding of the mismatched base-pairing interactions in DNA will help reveal genetic diseases and provide a theoretical basis for the development of targeted drugs. Here, we utilized mononucleotide fragment to simulate mismatch DNA interactions in a local hydrophobic microenvironment. The bipyridyl-type bridging ligands were employed as a mild stabilizer to stabilize the GG mismatch containing complexes, allowing mismatch to be visualized based on X-ray crystallography. Five single crystals of 2′-deoxyguanosine–5′–monophosphate (dGMP) metal complexes were designed and obtained via the process of self-assembly. Crystallographic studies clearly reveal the details of the supramolecular interaction between mononucleotides and guest intercalators. A novel guanine–guanine base mismatch pattern with unusual (high anti)–(high anti) type of arrangement around the glycosidic angle conformations was successfully constructed. The solution state 1H–NMR, ESI–MS spectrum studies, and UV titration experiments emphasize the robustness of this g–motif in solution. Additionally, we combined the methods of single-crystal and solution-, solid-state CD spectrum together to discuss the chirality of the complexes. The complexes containing the g–motif structure, which reduces the energy of the system, following the solid-state CD signals, generally move in the long-wave direction. These results provided a new mismatched base pairing, that is g–motif. The interaction mode and full characterizations of g–motif will contribute to the study of the mismatched DNA interaction.

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Induced‐Fit Recognition of CCG Trinucleotide Repeats by a Nickel–Chromomycin Complex Resulting in Large‐Scale DNA Deformation

Cited by 3 publications

References 36 publications

Parity-dependent hairpin configurations of repetitive DNA sequence promote slippage associated with DNA expansion

Parity-dependent hairpin configurations of repetitive DNA sequence promote slippage associated with DNA expansion

Long-Range Hairpin Slippage Reconfiguration Dynamics in Trinucleotide Repeat Sequences

The Research of G–Motif Construction and Chirality in Deoxyguanosine Monophosphate Nucleotide Complexes

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