DNA is composed of nucleic base pairs that form hydrogen bonds. Purines like guanine and adenine form hydrogen bonds with pyrimidines, cytosine, and thymine to form the DNA double-stranded helix structure. I-motif DNA is a different structure. Under acidic conditions, the cytosine pairs with another cytosine and causes the DNA to fold and form a different structure. Imagine tying your shoelaces together (conventional DNA structure), and one of the laces forms a knot with itself—that’s the i-motif DNA structure!
In 1993, Kalleh Gehring, Jean-Louis Leroy, and Maurice Guéron discovered the i-motif DNA structure in vitro under acidic conditions. However, the biological relevance of i-motif remained uncertain due to a lack of in vivo studies of i-motif. Mahdi Zeraati et al. (2018) proved that i-motif can form naturally in vivo. They generated and characterized an antibody that would directly visualize the i-motif structure in the nuclei of human cells, solidifying the presence of i-motifs in physiological conditions and their potential function in cellular processes.
The i-motif structure is produced from the folding of cytosine-rich nucleic acid sequences. I-motifs are formed by the base pairing of cytosine with protonated cytosine. As observed by Gehring et al. (1993), i-motifs present stability in acidic pH levels (optimal between pH 4.0 and 5.0). In vivo studies of i-motif sought to address the formation of i-motifs under physiological conditions (pH 7.0-7.4). In a study by Deep et al. (2025), i-motif formation was observed in the nuclei of cancer cell lines under physiological conditions, implying that other factors may play a role in i-motif formation and stability other than pH level, which has been intensively studied, such as temperature and molecular crowding.
The i-motif plays an important role in transcriptional regulation of gene expression, serving as a regulatory switch, leading to changes in the phenotype and cell cycle behavior. A novel practical application of i-motifs is in cancer therapy and drug development. I-motifs can be found in the promoter regions of oncogenes, or genes that, when mutated, can induce cancer. For example, in a promoter of BCL2, an anti-apoptotic gene, studies have shown that stabilizing i-motifs can enhance gene expression of BCL2, protecting cells from dying. Conversely, disrupting them with an i-motif destabilizer can downregulate gene expression, leading to apoptosis and tumor size reduction.
From mere DNA structures commonly observed under acidic conditions, studies on i-motifs continue to elucidate their role in gene regulation, cell function, and their clinical applications in pathophysiology and disease treatment. Current i-motif research is not limited to oncological studies but even extends to neurological and metabolic disorders, aging, epigenetic regulation, and other molecular biological and clinical applications.
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