G-quadruplex DNA found in human cells

DNA can tangle itself into strange shapes - including this four-stranded molecular knot...
24 February 2021

Interview with 

Ben Lewis, Imperial College London


Quadruple-helix DNA structure.


What shape is DNA? The helter-skelter double spiral you’re thinking of is mostly right. But sometimes DNA tangles itself into stranger shapes - and now scientists from Imperial College London have found evidence for one of these inside human cells. It’s called the G-quadruplex, and researcher Ben Lewis explained it to Phil Sansom...

Ben - You might know about the double helix. And if you know anything about it, you might know how it was one of the most pivotal discoveries in all of genetics. The story didn't end there, because DNA can actually adopt other structures. A lot of these are very unusual and wacky, but we're interested in one called a G-quadruplex; and the reason we're particularly interested in this is because it's stable and can form in the same conditions as inside our cells.

Phil - What is a G-quadruplex?

Ben - It's a quadruplex as opposed to the normal structure of DNA, which is a duplex. So duplex means we have two strands; and in the G-quadruplex instead we have four strands, the DNA wrapping back on itself four times, to form this structure which is often seen as being like a knot.

Phil - How strange!

Ben - It's certainly unusual, but there's all kinds of amazing DNA structures that people are interested in. Perhaps it's not the most surprising that one of those can actually form in the same conditions in ourselves.

Phil - How can you tell? DNA is very small!

Ben - Yes, so being able to see G-quadruplexes is the challenge. There's going to be so few of them compared to the rest of the DNA, and it obviously exists amongst a huge amount of other DNA; so we're trying to find a needle in a haystack, except that needle is also made of hay.

Phil - Then how do you do it?

Ben - So the normal way that you would try and find something inside a cell is by creating a probe which binds specifically to that thing you're looking for, and then gives out some signal that you can see. Most usefully you would do something fluorescent. But the problem with that is that you need a probe that's super specific, and there's just so little G-quadruplex DNA, it's really almost impossible to make a probe that's specific enough. So we've had to use a slightly more complicated approach to try and overcome this hurdle.

Their approach uses a fluorescent probe like Ben describes, but it measures the light in a different way.

Ben - Normally you would look at all the light that comes from one point. But instead we look at when it arrives at our detector, and this is called the fluorescence lifetime. The fluorescence lifetime is affected by the environment around our molecule. So we don't need a super specific probe for our G-quadruplex; we just need a probe that gives us a different florescence lifetime when it's bound to quadruplex DNA compared to all the other DNA. And that's what we've been able to make a probe that's able to do.

Phil - Right. So now that you can figure out where the G-quadruplexes are - when you look at human cells, what do you find?

Ben - There are quite a number of G-quadruplexes present in the sales we've studied. The way we've done this is by looking at the machinery that people think is handling and unwinding these G-quadruplexes in ourselves. And for the first time, we've actually been able to see that when you get rid of this machinery, you see a lot more of the G-quadruplex DNA inside those cells. As of right now, we don't really know exactly how many G-quadruplexes there are; but now that we have a new tool to use which allows us to look for these G-quadruplexes in living cells, we have the opportunity to start answering questions like that, and many others.

Phil - Another question then is: if you've got special machinery inside you that gets rid of this stuff, is it something that's only there by mistake, and it's a problem?

Ben - Well, our cells have a great knack for using all the tools available to it. So whilst you could see in some circumstances these knot-like structures getting in the way of our normal cells' processes, there are also a lot of potential ways in which the cell might use these quadruplex structures as markers that tell it when to potentially express specific genes, or for other uses that we haven't even imagined yet.

Phil - Like for what? Can you give me an example?

Ben - These G-quadruplexes could be used or abused in the case of cancer cells. There's a lot of sequences of DNA that could form G-quadruplexes just before genes that are vital to cancer cells, where the cells hijack these genes and use them to grow out of control into tumours. But at the same time, we've also seen ways in which the cells could use these G-quadruplexes to stop cancer in its tracks. This is particularly seen in the ends of our chromosomes, in a part called the telomeres; these are the protective caps that protect the end of the chromosome from damage, in the same way that the little plastic caps on your shoelace protect the ends from fraying. There's a lot of sequences there that could form G-quadruplexes, and these have been shown to actually be able to stop the machinery that cancer cells use to extend those caps indefinitely and help them become immortal. The formation of quadruplexes could actually put a halt to that process and prevent those cancer cells from successfully immortalising themselves.


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