What's new in DNA structure?

20 July 2020

Interview with 

Zoe Waller, University of East Anglia

DNA

Genes and DNA

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So far we’ve dwelled on the history of DNA, but what about the present and future? Since 1953 we’ve decoded all 3 billion letters of the human genetic code, learned to read DNA sequences incredibly fast, found ways to transfer genes from one organism into another to make vaccines and drugs rapidly and safely, and now we’re moving into the realms of editing an organism’s DNA. But scientists still remain very interested in the structure of DNA itself, because it has some special chemical properties, speaking with Chris Smith from the University of East Anglia, is Zoë Waller...

Zoë - So Rosalind Franklin, the data that she got showed that the structure of DNA was helical, it's composed of two strands, and these run in opposite directions to each other, and that the helix was not completely symmetrical. So one strand was slightly offset from the other. Using that data, Watson and Crick proposed a model, so what they suggested was only a model of DNA. It was widely accepted to be correct, but it wasn't actually shown in full detail until the 1980s where they used detailed X-ray crystallography structures to actually determine a more detailed vision of what the DNA molecule is. And then that showed that actually that model was pretty much spot on.

Chris - Obviously cells have something of a problem with their DNA though don't they? Because if one were to look at how much DNA is in a cell it's measured in meters, but the size of a cell is measured in fractions of a millimetre. So how do cells get around this?

Zoë - That is true. If you lined up all of the DNA in one cell, it would be about two metres long. Being able to compact the DNA enough to get it to fit inside the cell is a magnificent feat of biology. The DNA is wrapped around proteins and it's very, very tightly wound up. So what happens is when the DNA needs to be used or read, that unwinding, it's a bit like winding up a an elastic band for example. If you wind it again and again and again, and then you try and pull it apart, you'll find that that tension actually causes other parts of the elastic band to kind of crumple up and the DNA will do the same. And it actually forms other structures as well when this happens.

Chris - Does that affect how genes can be read or not? Because if you've got your elastic band analogy, a band wound up very, very tightly, if I wanted to see what was written on the inside surface of a bit of my elastic band, I'd have a hell of a job pulling it apart so I could actually see. And I suppose when you want to read a section of your genome, if it's wound up tight as a spring, that's going to be a problem.

Zoë - There are particular enzymes and proteins that help unwind the DNA. Even when those are working, the DNA needs to pull apart to become two separate strands. And it's when that happens, that DNA can actually form into alternative structures. And those are some of the ones that we are interested in my research group.

Chris - Like what?

Zoë - We are particularly interested in four-stranded structures. So when DNA contains a lot of one single base, for example, the base C or cytosine, that can form into four-stranded structures. Which are very much like a, almost like a knot these are called i-motifs, we're very much interested in that. And these form when cytosine, instead of base pairing with guanine or C base with G, actually base pairs with itself. So it forms an interaction with itself. And then this can actually result in different structures forming.

Chris - I'm just trying to get my head around that. So I'm envisaging two strands of DNA. And then in one place in the DNA, there's going to be this long chain of Cs, the letter C, one after the other. And you're saying that because of the chemistry of that long run of Cs, that those Cs can sort of fold out and distort and stick to themselves rather than what they should be doing. And this produces these rather strange knots in the DNA.

Zoë - Yes. So if you imagine a single strand or even a piece of string and then wrap it around twice around something, that's the kind of type of structure that you've got. It's a four-stranded structure, so you need to loop it round twice. Instead of having DNA, or double helical DNA, I like to think of it like a twisted ladder - so you imagine a ladder, twist it round - instead of having that type of structure, an i-motif is intercalated and that's what the I stands for. If you criss cross your fingers or intersect your fingers so they form a cross shape, that is what you have in the middle of the core of this DNA structure. So instead of it being like a ladder, it has crosses in the middle. So this structure is very tightly compact, and it's also much smaller in size compared to the equivalent single strand or double stranded DNA.

Chris - Are these common in cells? Do you see this normally? And what do they do?

Zoë - Well, that is a big question and one that we are very interested in. It is only a couple of years ago that these have been shown to exist in cells. It's thought that these structures play a role in how genes are read. Some evidence has been shown that if you help try to form the i-motif structure, you can actually help switch a gene on, but we're still learning about these things. And this is one of the reasons why we are very excited to work on it.

Chris - If you look at cells that have diseases, and I'm thinking particularly of genetic diseases like cancer, do you see more or fewer of these things? Might they be a hallmark of a cell that's going down the pathway towards cancer, and may they also therefore be a way in which you could control genes in cancer and potentially turn a cancer cell off?

Zoë - This is absolutely one of the things that people are interested in. One of the things that we are working on and we've been looking at is how these sequences that contain a lot of cytosine actually change as we age. As we get older, these cytosines are quite often deleted or mutated, so that means they're no longer a cytosine, they might be changed to a different base. This will change eventually the structure of DNA as well. So we're looking at how that affects aging and how it affects the structure of DNA and how this could potentially affect how genes are read. But then also through the progress of disease as well, diseases such as cancer, but also we are looking at diabetes as well.

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