Open research questions in DNA and Nucleic Acid Chemistry
100 unresolved questions extracted from the limitations and future-work sections of 257 DNA and Nucleic Acid Chemistry papers in our library. Each links back to the study that raised it.
What the literature leaves open
The study identifies the challenge of developing anticancer agents with improved selectivity and safety profiles. The study also notes the challenge of understanding the interaction of cAQ-mBen with mitochondrial G4-forming sequences. Another challenge is the limited sample size in the animal experiment, which precludes statistical demonstration of absence of toxicity.
In Vitro Binding to a Mitochondrial G-Quadruplex-Forming Sequence and Exploratory Acute Tolerability Assessment of a Cyclic Anthraquinone Anticancer Agent · 2026 · DOIThe gap is the lack of direct experimental evidence for the interaction of cAQ-mBen with a mitochondrial DNA-derived G4-forming sequence. The study aims to address this gap by characterizing the in vitro interaction of cAQ-mBen with the mitochondrial DNA-derived G4-forming sequence mt6363.
In Vitro Binding to a Mitochondrial G-Quadruplex-Forming Sequence and Exploratory Acute Tolerability Assessment of a Cyclic Anthraquinone Anticancer Agent · 2026 · DOIAlthough RNA has been predicted to be an off-target for numerous FDA-approved drugs, the extent and functional significance of RNA off-targeting among anticancer small molecules remain poorly understood.
Transcriptome-wide mapping reveals a non-canonical RNA-dependent mechanism of platinum cancer drugs · 2026 · DOISelective molecular recognition of dynamic nucleic acid structures is fundamental to DNA replication, yet the physical mechanisms by which intrinsically disordered protein domains achieve this selectivity remain poorly understood.
The intrinsically disordered C-terminal domain of bacteriophage T4 gp32 amplifies pre-existing conformational heterogeneity at DNA replication junctions · 2026 · DOIAbstract The role of nanoconfinement in regulating the folding of cytosine-rich DNA into i-motif structures under physiological pH conditions remains poorly understood.
Protamine, an arginine-rich protein, compacts DNA more tightly than histones in somatic cells, yet its sequence-specific binding remains unclear.
AT vs GC binding of protamine-template: A microscopic understanding through molecular dynamics and binding free energies · 2025 · DOIDespite rapid progress, synthetically recapitulating the nonequilibrium, spatially distributed responses of natural membrane-less organelles remains elusive.
Preliminary in vivo and in vitro studies suggest ASOs as a viable adjuvant therapy for high-grade gliomas, warranting further exploration in clinical trials.
Further investigation and clinical trials are warranted to validate ASOs as a transformative approach in neuro-oncology.
We observe that the microsecond timescale is insufficient to observe any transitions; only at millisecond timescales achieved via accelerated MD simulations do we find the inactive PR switches to the active state.
How nuclear receptors transition between active and inactive forms: An energetic perspective · 2024 · DOIThe ligand designed with lipophilic small-sized scaffolds bearing multipositive charges targeting the unique feature of high mitochondrial membrane potential (MMP) is lacking and most mitochondria-selective ligands are not G4-targeting.
Mitochondria-Selective Dicationic Small-Molecule Ligand Targeting G-Quadruplex Structures for Human Colorectal Cancer Therapy · 2024 · DOIDespite some mitochondria-selective ligands being reported for drug delivery against cancers, the ligand design is mostly limited to the triphenylphosphonium scaffold.
Mitochondria-Selective Dicationic Small-Molecule Ligand Targeting G-Quadruplex Structures for Human Colorectal Cancer Therapy · 2024 · DOIThe development of more advanced sequencing technologies is needed to sequence xenonucleic acids. The improvement of semi-synthetic organisms is necessary for use in bacterial synthesis of drugs. The exploration of potential applications of unnatural base pairs in fields such as aptamer enhancement and gene editing is needed.
The expansion of the genetic alphabet is a relatively new field with many challenges and possibilities. The incorporation of unnatural base pairs into nucleic acids is a complex process. The sequencing of xenonucleic acids is a major challenge.
Further studies on the combination of QN-302 with Olaparib. Investigation of QN-302's activity in other cancer types. Development of new G4 ligands with improved anticancer activity.
DNA damaging properties of G-quadruplex ligand QN-302 are potentiated by the DNA repair inhibitor Olaparib and mitigated by the molecular helicase PhpC · 2026 · DOIThe G4-coupled mechanism of BLM action remains to be fully understood. The role of RECQL1 in replication fork restart after exposure of human cells to the topoisomerase I inhibitor camptothecin is not fully understood.
DNA translocases that remodel stressed replication forks may play a role in the response to G-quadruplexes encountered during replicative DNA synthesis; however, it remains to be definitively shown that fork regression is elicited upon G4-induced stalling.
The development of harmonized ICH guidelines for oligonucleotides. The improvement of analytical techniques for oligonucleotide analysis. The development of more efficient purification methods.
The lack of harmonized ICH guidelines for oligonucleotides. The complexity of oligonucleotide structures makes analysis and impurity identification challenging.
The existence and relevance of long-looped G4s are uncertain due to deviations from the accepted G4 consensus sequence. Standard methods for identifying G4 sequences often penalize long loops or do not detect them at all.
Potential long-looped G-quadruplexes in the BCL-2 promoter and their implications in gene regulation · 2026 · DOIThe study does not investigate the biological significance of the ES2 state. The study only simulates the system for 200 ns. The study uses a limited number of systems.
Investigation of the biological significance of the ES2 state. Development of new methods for probing exchange rates. Investigation of the effects of other drugs on DNA base-pairing dynamics.
The susceptibility of DNA to enzymatic degradation - The need for more research on the potential applications of DNA hydrogels - The challenge of designing and implementing stimuli-triggered cascaded DNA conformation transitions
Recent Advances in Small Molecules-mediated DNA Conformations: From Structural Characteristics to Applications · 2026 · DOIFurther research on the potential applications of DNA hydrogels - Further research on the use of small molecules to mediate noncanonical DNA structures
Recent Advances in Small Molecules-mediated DNA Conformations: From Structural Characteristics to Applications · 2026 · DOIFurther studies are needed to fully characterize the binding properties of cNDI-CuGGHE to G4 structures. The development of other small-molecule ligands with improved binding affinity and specificity for G4 structures. The application of the CUT&RUN-like assay using cNDI-CuGGHE to study the role of G4 structures in gene regulation and genome stability.
Small-molecule-based CUT&RUN for G-quadruplex DNA using a cyclic naphthalene diimide–copper complex · 2026 · DOI
Most-cited papers in DNA and Nucleic Acid Chemistry
- Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid · Nature · 1953 · 10,604 citations
- Systematic Evolution of Ligands by Exponential Enrichment: RNA Ligands to Bacteriophage T4 DNA Polymerase · Science · 1990 · 9,254 citations
- Real-Time DNA Sequencing from Single Polymerase Molecules · Science · 2008 · 3,261 citations
- Sequence-Selective Recognition of DNA by Strand Displacement with a Thymine-Substituted Polyamide · Science · 1991 · 2,921 citations
- Design and self-assembly of two-dimensional DNA crystals · Nature · 1998 · 2,573 citations
- The Leucine Zipper: A Hypothetical Structure Common to a New Class of DNA Binding Proteins · Science · 1988 · 2,552 citations
- Overstretching B-DNA: The Elastic Response of Individual Double-Stranded and Single-Stranded DNA Molecules · Science · 1996 · 2,392 citations
- Calf thymus ds-DNA intercalation with pendimethalin herbicide at the surface of ZIF-8/Co/rGO/C3N4/ds-DNA/SPCE; A bio-sensing approach for pendimethalin quantification confirmed by molecular docking study · Chemosphere · 2023 · 173 citations
- G-quadruplex DNA structure is a positive regulator of MYC transcription · Proceedings of the National Academy of Sciences · 2024 · 136 citations
- G-quadruplex ligands in cancer therapy: Progress, challenges, and clinical perspectives · Life Sciences · 2024 · 133 citations
Most recent work
- DNA twist at high alkali ion concentrations: evidence against C-form DNA in solution · Nucleic Acids Research · 2026
- Novel Tetrahydroxanthylium-Based Ligands Targeting Mitochondrial DNA G-Quadruplex Structures for Concurrent Induction of Apoptosis and Inhibition of Autophagy in Liver Cancer · Journal of Medicinal Chemistry · 2026
- Retargeted serine integrases for one-step, precise integration of large DNA sequences in human cells · Nature Biotechnology · 2026
- Enhanced splicing modulation by NMA-modified antisense oligonucleotides · Nucleic Acids Research · 2026
- i-Motif, not G-quadruplex, stability regulates insulin expression · Nucleic Acids Research · 2026
- The Critical Role of the 2'-OH group in Phase Separation and Percolation Transitions of RNA · bioRxiv · 2026
- Unraveling Non-B DNA Structures in the Era of Telomere-to-Telomere Genomes · Annual Review of Genomics and Human Genetics · 2026
- DNA damaging properties of G-quadruplex ligand QN-302 are potentiated by the DNA repair inhibitor Olaparib and mitigated by the molecular helicase PhpC · Genome Biology · 2026
- Rare genetic diseases associated with G-quadruplex-induced replication stress · Communications Biology · 2026
- 1H R1ρ relaxation identifies a hidden intermediate in DNA base-pairing. · Nature Communications · 2026
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