Evaluation of i‐Motif Formation in the Serotonin Transporter‐Linked Polymorphic Region

Thorne, Bryony N.; Ellenbroek, Bart; Day, Darren J.

doi:10.1002/cbic.202000513

Cited by 3 publications

(4 citation statements)

References 26 publications

(74 reference statements)

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“…Recent studies have demonstrated that the DNA i -motif conformations can form at physiological pH in the nuclei of human cells as well as in the nuclei and chromosomes of invertebrates, corroborating the existence of i -motif structure in vivo. The prevalence of oligonucleotides with repetitive Cyt-rich sequences in genomic regions such as telomeres, centromeres, , and promoter areas of oncogenes − have facilitated both in vitro and in vivo laboratory characterization of i -motif structures in these regions of the human genome and stimulated enormous interest in elucidating the functional roles of the i -motif in biological systems and its potential for use in nanotechnological applications. , …”

Section: Introductionmentioning

confidence: 99%

“…The prevalence of oligonucleotides with repetitive Cyt-rich sequences in genomic regions such as telomeres, 8 centromeres, 9,10 and promoter areas of oncogenes 11−13 have facilitated both in vitro and in vivo laboratory characterization of i-motif structures in these regions of the human genome 6 and stimulated enormous interest in elucidating the functional roles of the i-motif in biological systems 14 and its potential for use in nanotechnological applications. 13,15 Among the myriad of key questions concerning the biochemistry of nucleic acid i-motif conformations are the type and optimum number of protonated (Cyt)H + (Cyt) base pairs required to form a thermodynamically stable i-motif architecture and how this number is influenced by posttranscriptional modifications. These pertinent questions can be answered by first focusing on gaining an in-depth knowledge of the factors that govern the structures, stabilities, and dynamics of the noncovalent interactions that stabilize the i-motif.…”

Section: ■ Introductionmentioning

confidence: 99%

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Influence of 5-Methylation and the 2′- and 3′-Hydroxy Substituents on the Base Pairing Energies of Protonated Cytidine Nucleoside Analogue Base Pairs: Implications for the Stabilities ofi-Motif Structures

2021

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Repetitive nucleic acid sequences, which occur in abundance throughout the mammalian genome, are of enormous research interest due to their potential to adopt fascinating and unusual molecular structures such as the i-motif. In remarkable contrast to the DNA double helix, i-motif conformations are stabilized by protonated cytosine base pairs, (Cyt)H + (Cyt), that are centrally located in the core of the i-motif and intercalated vertically in an antiparallel fashion. An in-depth understanding of how modifications influence the stability of i-motif conformations is a prerequisite to understanding their biological functions and the development of effective means of tuning their stability for specific medical and technological applications. Here, the influence of the 2′-and 3′-hydroxy substituents of the sugar moieties and 5-methylation of the cytosine nucleobases on the base-pairing interactions of protonated cytidine nucleoside analogue base pairs, (xCyd)H + (xCyd), are examined by complementary threshold collision-induced dissociation techniques and computational methods. The xCyd nucleosides examined include the canonical DNA and RNA cytidine nucleosides, 2′-deoxycytidine (dCyd) and cytidine (Cyd), as well as several modified cytidine nucleoside analogues, 2′,3′-dideoxycytidine (ddCyd), 5-methyl-2′-deoxycytidine (m 5 dCyd), and 5-methylcytidine (m 5 Cyd). Comparisons among these model base pairs indicate that the 2′-and 3′-hydroxy substituents of the sugar moieties have very little influence on the strength of the base-pairing interactions, whereas 5-methylation of the cytosine nucleobases is found to enhance the strength of the base-pairing interactions. The increase in stability resulting from 5-methylation is only modest but is more than twice as large for the DNA than RNA protonated cytidine base pair. Overall, present results suggest that canonical DNA i-motif conformations should be more stable than analogous RNA i-motif conformations and that 5-methylation of cytosine residues, a significant epigenetic marker, provides greater stabilization to DNA than RNA i-motif conformations.

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Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Influence of 5-Methylation and the 2′- and 3′-Hydroxy Substituents on the Base Pairing Energies of Protonated Cytidine Nucleoside Analogue Base Pairs: Implications for the Stabilities ofi-Motif Structures

2021

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“…The linkage polymorphic region of SERT contains two C-rich allelic variants that regulate susceptibility to depression by altering SERT expression levels. Both variants can form i-motifs; however, the mechanism requires further exploration ( Zhang et al, 2015 ; Thorne et al, 2021 ). As a key regulator of serotonin, i-motifs in the SERT-linkage polymorphic region will be an important pharmacological breakthrough for treating depression.…”

Section: Diseases Closely Associated With I-motifsmentioning

confidence: 99%

Emerging roles of i-motif in gene expression and disease treatment

et al. 2023

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As non-canonical nucleic acid secondary structures consisting of cytosine-rich nucleic acids, i-motifs can form under certain conditions. Several i-motif sequences have been identified in the human genome and play important roles in biological regulatory functions. Due to their physicochemical properties, these i-motif structures have attracted attention and are new targets for drug development. Herein, we reviewed the characteristics and mechanisms of i-motifs located in gene promoters (including c-myc, Bcl-2, VEGF, and telomeres), summarized various small molecule ligands that interact with them, and the possible binding modes between ligands and i-motifs, and described their effects on gene expression. Furthermore, we discussed diseases closely associated with i-motifs. Among these, cancer is closely associated with i-motifs since i-motifs can form in some regions of most oncogenes. Finally, we introduced recent advances in the applications of i-motifs in multiple areas.

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“…In addition to the TH promoter, the serotonin transporter-linked polymorphic region, which regulates serotonin transporter (SERT) gene expression, another important factor in neurological diseases and psychiatric disorders, also contains an i-motif-forming sequence [155]. This i-motif structure forms at neutral pH under molecular crowding conditions and could serve as an alternative target for SERT inhibition.…”

Section: Other Neurological Disordersmentioning

confidence: 99%

The i-Motif as a Molecular Target: More Than a Complementary DNA Secondary Structure

Brown

Kendrick

2021

Pharmaceuticals

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Stretches of cytosine-rich DNA are capable of adopting a dynamic secondary structure, the i-motif. When within promoter regions, the i-motif has the potential to act as a molecular switch for controlling gene expression. However, i-motif structures in genomic areas of repetitive nucleotide sequences may play a role in facilitating or hindering expansion of these DNA elements. Despite research on the i-motif trailing behind the complementary G-quadruplex structure, recent discoveries including the identification of a specific i-motif antibody are pushing this field forward. This perspective reviews initial and current work characterizing the i-motif and providing insight into the biological function of this DNA structure, with a focus on how the i-motif can serve as a molecular target for developing new therapeutic approaches to modulate gene expression and extension of repetitive DNA.

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Evaluation of i‐Motif Formation in the Serotonin Transporter‐Linked Polymorphic Region

Cited by 3 publications

References 26 publications

Influence of 5-Methylation and the 2′- and 3′-Hydroxy Substituents on the Base Pairing Energies of Protonated Cytidine Nucleoside Analogue Base Pairs: Implications for the Stabilities ofi-Motif Structures

Influence of 5-Methylation and the 2′- and 3′-Hydroxy Substituents on the Base Pairing Energies of Protonated Cytidine Nucleoside Analogue Base Pairs: Implications for the Stabilities ofi-Motif Structures

Emerging roles of i-motif in gene expression and disease treatment

The i-Motif as a Molecular Target: More Than a Complementary DNA Secondary Structure

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