Abstract
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.
Highlights
In 1953, Watson and Crick first published the structure of the DNA double helix [1].They described a DNA molecule as a right-handed, twisted coil composed of a purine and pyrimidine inner core held together by hydrogen bonds, with a sugar–phosphate backbone that extended from these paired bases
Human telomeric i-motif sequences were used as a model, the findings provide a proof of concept that α-syn may exert its cellular function through interactions with i-motifs [151]
Major technological advances to detect and evaluate i-motif formation have contributed to the understanding of i-motif biology and addressed the longstanding question of whether DNA adopts such structures within cells
Summary
In 1953, Watson and Crick first published the structure of the DNA double helix [1]. They described a DNA molecule as a right-handed, twisted coil composed of a purine and pyrimidine inner core held together by hydrogen bonds, with a sugar–phosphate backbone that extended from these paired bases. Similar to the guanines in the G4, base pairing of cytosines occurs of cytosines occurs via Hoogsteen hydrogen bonds; since the formation via Hoogsteen hydrogen bonds; since the formation of i-motif structures of imotif requires the protonation of cytosines, form more requires the structures protonationalso of cytosines, i-motifs form more readily ati-motifs acidic pH. I-motif folded structure; and tracts and (C) the C-rich sequence that gives rise to an i-motif with the pairing pattern of cytosine (C) the illustrated. Many factors are recognized to influence whether a nucleotide sequence is likely to form an i-motif, including the local, molecular environment, loop length and base composition, and epigenetic modification. The specific nucleotide sequence of the i-motif-forming region impacts the stability of the consequent structure, where, for example, the melting temperature of an i-motif increases with the number of cytosines in sequence [29,30]. The presence of i-motif sequences within CpG islands, which are well-known sites of methylation, supports this finding and indicates that methylation may contribute to i-motif formation within living cells [37,38,39]
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