Function:
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I-motifs are postulated to play a role in gene regulation and expression in the cell. Large tracts of G/C-rich DNA exist near transcriptional start sites in the genome, and are present in a wide variety of organism genomes, suggesting that C-rich tracts have a biological function. Promoter regions of certain genes are C-rich, especially in oncogenes, which strengthens the suggestion that i-motifs function as gene transcription regulators.[1][2] Furthermore, i-motif hTelo was found within regulatory regions of the genome during the late G1 phase of the cell reproduction cycle, indicating that i-motifs are involved in gene promotion and regulation. I-motifs may also act as molecular scaffolds to aid in transcription factor binding during gene transcription by aiding promoters such as BCL2 in attaching to the correct DNA sequence. Increased i-motif expression did not coincide with increased G-quadruplex expression, which instead increases during the S phase. This indicates that G-quadruplex and i-motifs are not complementary structures despite their complementary sequences and are instead mutually exclusive and serve opposite roles in gene expression regulation. Although G-quadruplex and i-motifs are not complementary structures, G-rich 3' terminal ends can lead to its complementary DNA strand to be C-rich, which can form an i-motif, which can lead to telomerase inhibition.[3]There was also evidence that i-motifs could interfere with DNA repair and replication. Tang et al. performed an experiment where sequences that encourages i-motif formation in a DNA strand being replicated by DNA polymerase. The DNA polymerase was stalled, which implies i-motifs can impede DNA replication and repair.[4]
The interaction of i-motifs with ligands also affects function. The first known selective ligand to bind with I-motif DNA is Carboxyl-modified single-walled carbon nanotubes (CSWNTs). The ligand binds to the 5' end major groove of DNA to induce the i-motif. Once bound with CSWNT, i-motifs were found to interfere with telomerase and telomere functions in vitro and in vivo in cancer cells.[5]The binding of CSWNT to I-motif DNA increases the molecule's thermal stability at acidic pH by a significant amount. In this way, the ligand supports the formation of I-motif DNA over the Watson-Crick base pairing at pH 8.0.[6] This is significant because Until recently it was not clear whether I-motifs naturally existed in DNA due to their low stability at physiological pH; i-motifs were discovered in vivo in human DNA in 2018. Human telomeric DNA (hTelo) can form an i-motif secondary structure in vitro. Zeraati et al. confirmed the presence of i-motif hTelo in human DNA using a fluorescent marker called iMab.It has been since then detected in silkworms in the G1 stage in both acidic and neutral conditions.[4] Furthermore, many proteins and ligands fundamental to gene expression recognize C-rich oligonucleotides, such as Poly-C-binding protein (PCBP) and heterogeneous nuclear ribonucleoprotein K (HNRPK).
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- ^ Fleming, Aaron M.; Ding, Yun; Rogers, R. Aaron; Zhu, Judy; Zhu, Julia; Burton, Ashlee D.; Carlisle, Connor B.; Burrows, Cynthia J. (2017-03-21). "4n–1 Is a "Sweet Spot" in DNA i-Motif Folding of 2′-Deoxycytidine Homopolymers". Journal of the American Chemical Society. 139 (13): 4682–4689. doi:10.1021/jacs.6b10117. ISSN 0002-7863.
- ^ Wright EP, Huppert JL, Waller ZAE (2017) Identification of multiple genomic DNA sequences which form i-motif structures at neutral pH. Nucleic Acids Res 45: 2951–2959.
- ^ Amato, Jussara; Iaccarino, Nunzia; Randazzo, Antonio; Novellino, Ettore; Pagano, Bruno (2014-06-24). "Noncanonical DNA Secondary Structures as Drug Targets: the Prospect of the i-Motif". ChemMedChem. 9 (9): 2026–2030. doi:10.1002/cmdc.201402153. ISSN 1860-7179.
- ^ a b Tang, Wenhuan; Niu, Kangkang; Yu, Guoxing; Jin, Ying; Zhang, Xian; Peng, Yuling; Chen, Shuna; Deng, Huimin; Li, Sheng; Wang, Jian; Song, Qisheng (2020-03-05). "In vivo visualization of the i-motif DNA secondary structure in the Bombyx mori testis". Epigenetics & Chromatin. 13 (1). doi:10.1186/s13072-020-00334-y. ISSN 1756-8935.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Chen, Yong; Qu, Konggang; Zhao, Chuanqi; Wu, Li; Ren, Jinsong; Wang, Jiasi; Qu, Xiaogang (2012-01). "Insights into the biomedical effects of carboxylated single-wall carbon nanotubes on telomerase and telomeres". Nature Communications. 3 (1). doi:10.1038/ncomms2091. ISSN 2041-1723.
{{cite journal}}: Check date values in:|date=(help) - ^ Sushmita Nautiyal; Vishal Rai; Sudipta Bhat; Ravi Kumar; Mudasir Mohd Rather; M.Sankar. I-Motif Dna: Significance and Future Prospective. Exploratory Animal and Medical Research 2020, 10 (1), 18–23.
Applications:
Many biomedical applications of i-motif structures include cancer therapy and treatments, gene regulation and drug delivery systems. Currently, i-motif applications include drug delivery systems, bio-sensing, and molecular switches.
Gold nano-particles conjugation have been developed as a pH-induced drug delivery system. A study done using DNA conjugated gold nanoparticles (DNA-GNP) created a DNA-GNP with stretched of C-rich single-stranded DNA to take advantage of i-motif formation in cancer cell uptake and drug release. When the DNA-GNP equipt with possible i-motif formation enters a normal cell, no change takes place as the cell has a normal biological pH. But when the DNA-GNP enters a cancer cell, it encounters an acidic pH and induces i-motif conformation, triggering doxorubicin (DOX), an effective anticancer drug against leukemia and Hodgkin's lymphoma, release into the cell..[1] This method can also be used for biological sensing and diagnosis.
The utilization of i-motifs as colormetric and ratiometric sensors for glucose levels. A glucose detection system, Poly(24C)-MB, is based on the conformational change i-motifs undergo when pH changes. When glucose is oxidized pH levels decrease, which induces i-motif DNA. The dye of the system, methylene blue (MB) can't bind when i-motifs are induced, giving rise to a color change that is easily visible.This system is simple, cost-effective and precise due to i-motif conformation.[2]
A study at the University of Bonn explains how i-motifs can be utilized as molecular switches. They used I-motif folding to tighten and loosen a ring of DNA. A circular ring of DNA was synthesized, with certain regions of C-rich DNA. At a pH of 5, these regions contracted to form i-motifs, tightening the ring in a fashion similar to closing a trash bag. At a pH of 8 the I-motif regions collapsed back into their linear forms, relaxing the ring. DNA rings that can tighten and loosen based on pH can be used to build more complex structures of interlocking DNA like catenanes and rotaxanes. Another study showed that single-walled carbon nanotubes (CSWNTs), commonly used to carry drugs in the body, induce I-motif formation in human telomeric DNA. Researches modified C-rich human telomeric DNA by attaching a redox active methylene blue group to the 3′ end and an electrode to the 5′ end. In the I-motif conformation this modified DNA strand produces a large increase in Faradaic current. This biosensor only reacts to CSWNTs, allowing researchers to detect a specific type of carbon nanotube with a direct detection limit of 0.2 ppm.
Further application studies include cancer drug therapies, because there is a low pH inside cancer cell endosomes that i-motifs can thrive in.[3] Utilizing i-motifs as a delivery system or interference with cancer cell telomere activity is are viable alternatives being pursued in medicine. Other topics of inquiry on i-motif efficiency in cancer cell regulation and death include ligand effects.
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- ^ Song, Lei; Ho, Vincent H.B.; Chen, Chun; Yang, Zhongqiang; Liu, Dongsheng; Chen, Rongjun; Zhou, Dejian (2013-02). "Drug Delivery: Efficient, pH-Triggered Drug Delivery Using a pH-Responsive DNA-Conjugated Gold Nanoparticle (Adv. Healthcare Mater. 2/2013)". Advanced Healthcare Materials. 2 (2): 380–380. doi:10.1002/adhm.201370008. ISSN 2192-2640.
{{cite journal}}: Check date values in:|date=(help) - ^ Wang, Qin; Dai, Tianyue; Sun, Pengfei; Wang, Xiayan; Wang, Guangfeng (2020-08). "A colorimetric and ratiometric glucose sensor based on conformational switch of i-motif DNA". Talanta Open. 1: 100001. doi:10.1016/j.talo.2020.100001. ISSN 2666-8319.
{{cite journal}}: Check date values in:|date=(help) - ^ Webb, Bradley A.; Chimenti, Michael; Jacobson, Matthew P.; Barber, Diane L. (2011-08-11). "Dysregulated pH: a perfect storm for cancer progression". Nature Reviews Cancer. 11 (9): 671–677. doi:10.1038/nrc3110. ISSN 1474-175X.