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

Brown, Susie L.; Kendrick, Samantha

doi:10.3390/ph14020096

Cited by 57 publications

(51 citation statements)

References 161 publications

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“…Furthermore, a number of studies show that i-motifs function as molecular switches in the regulation of DNA transcription ( Brown and Kendrick, 2021 ). Depending on the specific promoter region, the unique i-motif sequence, and the associated transcription factors, i-motifs have the potential to act as an activator or repressor of transcription.…”

Section: Resultsmentioning

confidence: 99%

Remodeling the conformational dynamics of I-motif DNA by helicases in ATP-independent mode at acidic environment

Gao

Zheng

et al. 2022

iScience

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Summary I-motifs are noncanonical four-stranded DNA structures formed by C-rich sequences at acidic environment with critical biofunctions. The particular pH sensitivity has inspired the development of i-motifs as pH sensors and DNA motors in nanotechnology. However, the folding and regulation mechanisms of i-motifs remain elusive. Here, using single-molecule FRET, we first show that i-motifs are more dynamic than G4s. Impressively, i-motifs display a high diversity of six folding species with slow interconversion. Further results indicate that i-motifs can be linearized by Replication protein A. More importantly, we identified a number of helicases with high specificity to i-motifs at low pH. All these helicases directly act on and efficiently resolve i-motifs into intermediates independent of ATP, although they poorly unwind G4 or duplex at low pH. Owing to the extreme sensitivity to helicases and no need for ATP, i-motif may be applied as a probe for helicase sensing both in vitro and in vivo .

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Section: Resultsmentioning

confidence: 99%

Remodeling the conformational dynamics of I-motif DNA by helicases in ATP-independent mode at acidic environment

Gao

Zheng

et al. 2022

iScience

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“…Multiple G-tetrads π-stack upon each other to form a G4 with loops arising from intervening nucleotides between adjacent G-tracts (Figure 3D ) ( 63 , 64 ). G4s can be intramolecular where they form from a single DNA strand, or intermolecular where they consist of two or four separate DNA strands ( 56 , 57 ). In contrast, i-motif structures form within certain C-rich sequences through hemi-protonated cytosine–cytosine, or C···C + , base pairings (Figure 3E ).…”

Section: Non-canonical Dna Secondary Structures As Modulators Of Gene Expressionmentioning

confidence: 99%

Modulating gene expression in breast cancer via DNA secondary structure and the CRISPR toolbox

et al. 2021

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Breast cancer is the most commonly diagnosed malignancy in women, and while the survival prognosis of patients with early-stage, non-metastatic disease is ∼75%, recurrence poses a significant risk and advanced and/or metastatic breast cancer is incurable. A distinctive feature of advanced breast cancer is an unstable genome and altered gene expression patterns that result in disease heterogeneity. Transcription factors represent a unique therapeutic opportunity in breast cancer, since they are known regulators of gene expression, including gene expression involved in differentiation and cell death, which are themselves often mutated or dysregulated in cancer. While transcription factors have traditionally been viewed as ‘undruggable’, progress has been made in the development of small-molecule therapeutics to target relevant protein–protein, protein–DNA and enzymatic active sites, with varying levels of success. However, non-traditional approaches such as epigenetic editing, transcriptional control via CRISPR/dCas9 systems, and gene regulation through non-canonical nucleic acid secondary structures represent new directions yet to be fully explored. Here, we discuss these new approaches and current limitations in light of new therapeutic opportunities for breast cancers.

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“…The strand complementary to a G4-forming DNA motif is a C-rich sequence that can fold in another four-stranded structure called the i-motif (iM or i-DNA) [ 14 ]. This is composed of two head-to-tail, intercalated, parallel-stranded duplexes held together by hemi-protonated cytosine-cytosine (C-C + ) base pairs ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

“…Many studies, focused on disentangling the biological roles of G4 and iM structures, demonstrate that such structures can be considered as molecular targets in cancer therapies [ 14 , 18 , 19 ], leading to significant therapeutic advantages in the treatment of cancer. For example, direct evidence of the role of DNA G4s in gene regulation has been provided, showing that oncogene promoter activity is generally repressed using G4s stabilizers, while destabilization of G4s generally leads to increased gene transcription [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Bis-Triazolyl-Pyridine Derivatives as Noncanonical DNA-Interacting Compounds

Porzio

Galli

Amato

et al. 2021

IJMS

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Besides the well-known double-helical conformation, DNA is capable of folding into various noncanonical arrangements, such as G-quadruplexes (G4s) and i-motifs (iMs), whose occurrence in gene promoters, replication origins, and telomeres highlights the breadth of biological processes that they might regulate. Particularly, previous studies have reported that G4 and iM structures may play different roles in controlling gene transcription. Anyway, molecular tools able to simultaneously stabilize/destabilize those structures are still needed to shed light on what happens at the biological level. Herein, a multicomponent reaction and a click chemistry functionalization were combined to generate a set of 31 bis-triazolyl-pyridine derivatives which were initially screened by circular dichroism for their ability to interact with different G4 and/or iM DNAs and to affect the thermal stability of these structures. All the compounds were then clustered through multivariate data analysis, based on such capability. The most promising compounds were subjected to a further biophysical and biological characterization, leading to the identification of two molecules simultaneously able to stabilize G4s and destabilize iMs, both in vitro and in living cells.

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

Cited by 57 publications

References 161 publications

Remodeling the conformational dynamics of I-motif DNA by helicases in ATP-independent mode at acidic environment

Remodeling the conformational dynamics of I-motif DNA by helicases in ATP-independent mode at acidic environment

Modulating gene expression in breast cancer via DNA secondary structure and the CRISPR toolbox

Synthesis and Characterization of Bis-Triazolyl-Pyridine Derivatives as Noncanonical DNA-Interacting Compounds

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