Reverse Hoogsteen base pairing…..Wikipedia Commons

I know some of my biases. One of them is knee-jerk skepticism about taking little-tested scientific results and blowing them up to “…a cure for cancer” or “…revolutionize the electronics industry.” However, like most people I also have a bias to be curious about interesting, if somewhat unusual scientific findings. So what happens when I encounter something like “…an alternate DNA structure”?

Watson in his sleep and Crick in his grave, will be rolling double helixes. An alternate structure of normal DNA…for real? Yes. This discovery, made by a team of researchers from the University of California, Irvine (USA) and the University of Michigan (USA) and published in the journal Nature January 26, 2011 [Transient Hoogsteen base pairs in canonical duplex DNA] involves a new capability of nuclear magnetic resonance (NMR) machines and something most people have never heard of (including me): Hoogsteen base pairs.

Like many people I learned about DNA, the double helix, and base pairs while still a teenager. It’s a basic part of high school and biology tutoring for AP classes. I drilled to memorize cytosine (C), guanine (G), adenine (A), and thymine (T) and how they paired-up into A-T and G-C. These base pairs formed the ‘steps’ of the ‘ladder’ made by the twisting double helix. When not overly tired and sober I still remember all of it. However, nobody mentioned that there was another kind of base pairing.

It was discovered by the biologist Karst Hoogsteen in 1963. In effect, the Hoogsteen base pair is a ‘normal’ Watson-Crick base pair (usually A-T) flipped-over like an upside-down step on a ladder. In biochemistry this is not a trivial shift. It changes the geometry and allows for truly exotic formations such as a triple helix or even quadruplex structures. Since the shape of DNA with its many contortions is crucial for the ability to interact with various types of RNA, and hence the creation of specific proteins; this kind of radical shift within the structure of DNA could have a profound impact.

The obvious question is: Why hasn’t this been highlighted before? The answer is, mainly, that Hoogsteen base pairs were known to exist primarily in RNA and had been observed in DNA only when there was damage to the DNA structure, or something else like a protein or drug was bound to it. In RNA the Hoogsteen base pairs have been studied fairly extensively. They are considered an “excited state” and are useful to observe unusual protein binding. In DNA the Hoogsteen base pairing, which by the way has two forms, normal and reverse, was considered an anomaly.

The new research changes that consideration. By using an adapted nuclear magnetic resonance (NMR) device, the researchers were able to observe the chemical shifts associated with the formation of Hoogsteen base pairs. It was discovered that normal DNA undergoes these shifts about 1% of the time and they last only milliseconds. Conventional X-ray and NMR techniques couldn’t see these fleeting changes.

The presence of Hoogsteen base pairs in normal DNA, even if evanescent, indicate a new dimension to the configuration of DNA. As the lead researcher, Hashim Al-Hashimi (University of Michigan) put it:

“Together, these data suggest that there are multiple layers of information stored in the genetic code.”

Because critical interactions between DNA and proteins are thought to be directed by both the sequence of bases and the flexing of the DNA molecule, these excited states represent a whole new level of information contained in the genetic code.

[Source: Astrobiology Magazine]

I don’t want to let this slip by – “multiple layers of information.” In short, DNA is even more complex than suspected. To me, this sounds like opening the book of DNA code and discovering that it’s printed on origami. At this point, if I were a geneticist or a biochemist, I would be doing a slack-mouthed OMG. As these researchers mention, there may be other short-lived but significant excited states in DNA and RNA.

Add this information to the new findings about the importance of DNA configuration:

[SciTechStory: Histones: DNA packaging and much more]
[SciTechStory: In the helix grooves]

One suspects a ‘tip of the iceberg’ situation. Certainly, the more scientists learn about the role of DNA configuration, the more complex and subtle becomes the mechanism of protein formation via RNA (in its many forms) and the role of epigenetics.

Right now, there’s not much more than speculation. While it might just be my bias for the unexpected, I’d say this is an area of research that bears tracking.