Double helices, DNA dynamics, and I-motifs

Most are familiar with the classic Franklin-Watson-Crick DNA double helix; it shows up all over the place. The first appearance of the double helix in popular culture was a painting by Salvador Dalí in 1953 (in the painting, it’s on the left under the depiction of the prophet Isaiah), and I think the first time I saw a double helix may have been the film Jurassic Park (near the end of the clip).

The classic DNA double helix, the form that occurs most commonly in nature, is a right-handed helix known as B-DNA. “Handedness” refers to which way the helix twists. If a helix is right-handed, you can point your right thumb along the axis of the helix, and the turns of the helix will follow the curve of your fingers. Another way to distinguish right- from left-handed helices is to imagine yourself walking up the helix like a flight of stairs and then ask yourself whether you’d place your right or left hand on the “railing.” Whenever I come across a DNA helix in popular media or science journalism, I always like to check whether they’ve given it the “right” handedness. There have been some pretty egregious examples of people getting it wrong.

Of course, this is biology we’re talking about here, so there’s bound to be exceptions that prove the rule. Although B-DNA may be the most common form, DNA can adopt many different shapes or “conformations.” Some of these are shown below.

Alternative DNA conformations. From left to right: A-DNA, B-DNA, Z-DNA, G-4 motif, i-motif. The structures correspond to  PDB entries  440D, 5EJ1, 4OCB, 1K8P, and 1EL2, respectively.

Alternative DNA conformations. From left to right: A-DNA, B-DNA, Z-DNA, G-4 motif, i-motif. The structures correspond to PDB entries 440D, 5EJ1, 4OCB, 1K8P, and 1EL2, respectively.

The three DNA conformations on the left are double-stranded forms known to exist in nature; although A- and Z-DNA were once thought only to be possible in vitro (in a test-tube), we now know that they can exist in cells and have or reflect important biological functions. Z-DNA is a left-handed helix; try comparing the handedness using one of the above tests.

The fourth DNA conformation pictured is called a G-quadruplex, or G-4 motif. Here, four guanine bases form a single, planar hydrogen bonding network called a “G-tetrad;” three of these are stacked in the structure above to form the G-4 motif. This particular G-4 motif is comprised of 2 strands of DNA, but G-4 motifs can be made of 4 separate strands or even a single strand. G-4 motifs do occur in living cells and seem to play a role in regulating and maintaining telomeres, which are specialized regions at the ends of chromosomes.

The DNA structure shown at the far right is known as an i-motif. The “i” comes from the presence of intercalated cytosine:cytosine bonds. This structure is particularly interesting because it can be formed by a single strand of DNA folded into a box-like quadruplex structure, with alternating C:C bonds occurring between the opposite “corners” of the “box.”

Because one of the cytosines in each pair must be hemiprotonated, these structures form more readily at low pH, when there is a greater abundance of free H+ in solution. Certain cytosine-rich sequences have long been known to form i-motifs in vitro, but researchers have been skeptical about the possibility that these motifs occur in living cells, given the requirement for special conditions. However, a recent study by Mahdi Zeraati et al. demonstrates that i-motifs occur in living cells. The research group from Australia used an antibody-based approach to show that i-motifs are present, and interestingly, appear at higher frequency during certain stages of the cell cycle, specifically the G1/S boundary and the early S phase, which is when DNA replication begins. They also show that i-motifs appear in telomeres, in the regulatory regions of some genes, and when cells are exposed to high concentrations of carbon dioxide.

Given that i-motifs occur at different frequencies throughout the cell cycle or under different conditions, it is likely that these structures are dynamic, forming and unforming depending on the conditions. It is fun to speculate what the purpose of these structures might be, although little is known about their specific function. Are they recognized or bound by some regulatory protein? Do they play a role in telomere identity or maintenance, as G-4 motifs are thought to? Could their function be related to the double-stranded context in which they would occur? It is also fun to imagine what the dynamic formation of these structures might look like. Below, we can see a stretch of typical B-DNA, with one strand morphing into an i-motif structure.

Uploaded by Scientific Studios on 2018-06-13.