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History/Discovery

I-motif DNA, short for intercalated-motif DNA, are cytosine-rich four-stranded quadruplex DNA structures, similar to the G-quadruplex structures that are formed in guanine-rich regions of DNA. This structure was first discovered in 1993 by Maurice Guéron at l'École Polytechnique in Palaiseau, France, was found when two antiparallel doubled stranded DNA complexes with cystosine-protonated cytosine (C·C*) base pairs became associated with one another. This formed a complex 4- stranded DNA complex. The structure was originally found only in vitro, usually at a slightly acidic pH, but was recently discovered in the nuclei of human cells. During their media release in April of 2018, Dr. Mahdi Zeraati and colleagues mentioned that these complexes are constantly forming and dissociating due to their constantly changing temperatures, which could play a role in its function in regulation of gene expression and cell reproduction. Although the exact function of these structures is unknown, the transient nature of these molecules gives insight regarding the biological function of these molecules. Found primarily in the G1 phase of the cell cycle and in promoter regions, i-motif complexes could potentially affect which gene sequences are read and could play a role in determining which genes are switched on or off. Other experimentation is in progress to determine the role of i-motif DNA in nanotechnology using i-motifs as biosensors and nanomachines, and has even been seen to play a role in the advancement of cancer therapy.

Structure

The structure of this molecule consists of various tracts of oligodeoxynucleotides strands that contain mostly cytosine residues. The interactions between these molecules occur by the hemiprotonation of cytosine residues and non-Watson Crick base pairing.There are two main intercalated topologies that i-motifs can be classified in: 3'-E, when the outmost C:C+ base pair is at the 3'-end, and 5'-E, where the outermost C:C+ base pair is at the 5'-end. When comparing the two topologies, the 3'-E topology would be more stable due to increased sugar-sugar contacts. This occurs due to the difference in Van der Waals energy contribution between the two topologies. The interactions of the sugar-sugar contacts along the narrow grooves allows for optimal backbone twisting, which ultimately contributes to formation of stacking bases and the stability of the molecule. However, the overall stability of i-motif structures is dependent on the number cytosine residues that are interacting with each other. This means that as more cytosine residues interact through hydrogen bonding, the more stable the molecule will be. Other factors that affect the stability of the molecules include temperature, salt concentration and pH of the environment. While many i-motif complexes are most stable at a slightly acidic pH (between 4.2 and 5.2, some i-motifs have been found to form at neutral pH, when a free proton is used by the nucleic acids during the folding process. These particular i-motif complexes are found under particular conditions, including low temperature (4°C), molecular crowding, negative superhelicity, and the introduction of silver(I) cations. Maintaining a negative superhelicity is crucial for the stabilization of i-motifs at a neutral pH. I-motif structures have also been found to form under biological conditions.

One characteristic structural component of i-motif structures found in the NOESY cross peaks. Only i-motif DNA structures have short HI'-HI' distances as well as short amino proton H2'/H2" inter-residue distances. This reveals the proximity of the hemiprotonated residues and how they interact with one another.

Using the genomic sequences found in various organism, such as the tetrahymena species, the sequence found in the genome, [CCCCAAA]3CCCC, had the capability to form the tetramic complex. This formation was compared to the formation of the synthesized oligodeoxynucleotides, which introduced the idea that these complexes had the capability of forming within organisms.

These structures have been discovered in many different locations of the cell including the nuclei, the cytoplasm, and in telomeres and promoter sights. It can also be found in cell processes such as the G1 phase of the cell cycle.

A new antibody fragment (iMab) was created and was found to have highly specific binding affinity for i-motif complexes, but did not bind to other dNA structures. This tool was used to

Applications

Due to the structural and functional components of the i-motif structure, many applications have been investigated, including cancer therapy and theranostics. Because i-motif can play a role in the regulation and detection of specific ligand binding, this could be used in regulating the vascular epithelial growth factor (VEGF). In a study by Takahashi et al., it was found that by using C-SWNTs, telomerase activity could be inhibited, which could potentially lead to apoptosis of cancer cells. This is due to the