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There’s more to DNA than just the double helix we know and love: under some conditions this familiar molecule can take on unfamiliar forms, each of which can have a different impact on our health.

Hosted by: Hank Green

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Sources:
General overviews of alternate DNA structures:
https://www.intechopen.com/books/dna-replication-current-advances/dna-structure-alphabet-soup-for-the-cellular-soul
https://www.ncbi.nlm.nih.gov/books/NBK6545/
http://people.bu.edu/mfk/restricted566/dnastructure.pdf

B-DNA and history of the double helix:
https://www.nature.com/scitable/topicpage/discovery-of-dna-structure-and-function-watson-397/

A-DNA:
https://journals.iucr.org/q/issues/1953/08-09/00/a00979/a00979.pdf

Z-DNA:
https://www.nature.com/articles/s42003-018-0237-x

H-DNA:
https://www.pnas.org/content/pnas/101/37/13448.full.pdf

G-quadruplexes:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516791/

Image Sources:
https://commons.wikimedia.org/wiki/File:Base_pair_GC.svg
https://commons.wikimedia.org/wiki/File:Base_pair_AT.svg
https://commons.wikimedia.org/wiki/File:DNA_orbit_animated.gif
https://commons.wikimedia.org/wiki/File:A-DNA_orbit_animated.gif
https://commons.wikimedia.org/wiki/File:Z-DNA_orbit_animated.gif
https://www.istockphoto.com/vector/dna-gm477462523-36133444
https://www.istockphoto.com/photo/chromatin-strand-and-isolated-nucleosome-dna-histones-gm1169905740-323575931
https://commons.wikimedia.org/wiki/File:A-B-Z-DNA_Side_View.png
https://commons.wikimedia.org/wiki/File:Adna3.ogv
https://commons.wikimedia.org/wiki/File:0323_DNA_Replication.jpg
https://commons.wikimedia.org/wiki/File:DNA_replication_split.svg
https://www.istockphoto.com/photo/abstract-glittering-dna-helix-with-depth-of-field-over-dark-space-background-gm1201193016-344376611
https://commons.wikimedia.org/wiki/File:TriplexDNA(1BWG).png
https://www.istockphoto.com/photo/the-fracture-of-dna-molecular-gm450571643-24790953
https://www.istockphoto.com/photo/illustration-of-a-damaged-ribonucleic-acid-or-dna-strand-gm923218260-253424716
https://www.istockphoto.com/photo/yellow-and-blue-shoelace-gm120499022-15977723
https://www.istockphoto.com/photo/telomere-gm670202484-122541287
https://www.istockphoto.com/photo/chromosomes-gm173851340-8968775
https://commons.wikimedia.org/wiki/File:Guanin.svg
https://commons.wikimedia.org/wiki/File:G-quadruplex.svg
https://commons.wikimedia.org/wiki/File:Telomer-structure.gif
https://commons.wikimedia.org/wiki/File:Basic_units_of_chromatin_structure.svg
https://commons.wikimedia.org/wiki/File:Cytosin.svg
https://commons.wikimedia.org/wiki/File:RNA_i-motif.gif
https://commons.wikimedia.org/wiki/File:Holliday_junction_coloured.png
[♪ INTRO].

Even if you have not taken a science class in years, you probably know what DNA looks like. Mostly because it’s the twisty thing that’s basically a universal shorthand for “sciencey subjects are being discussed." Well, it turns out that’s doing life’s most crucial molecule a bit of a disservice.

Because yes, DNA is twisty… but let’s not put it in a box. That’s not all it can do. In fact, there’s a structure of DNA for nearly every letter of the alphabet.

And because structure creates function in molecular biology, all those weird shapes do something different in our bodies -- and mean something different for our health. So let’s start at the beginning: with B-DNA. Yeah, B-DNA comes first.

There is an A-DNA, but it’s not the first one. This is the double helix we all know and love -- but it’s still got a few surprises. The structure was proposed by Watson and Crick back in 1953, based on data collected by Rosalind Franklin.

But it was actually just a theoretical model for decades, until definitive experimental support was found in the ‘80s. It’s got two strands twisting around each other in a neat, regular fashion. Specifically, the B-DNA double helix is right-handed, meaning it twists from lower left to upper right.

Which actually has nothing to do with hands, but… here we are. The two strands are also unevenly spaced, such that there are two different sized gaps between them -- a major groove and a minor groove. And there are just over ten base pairs in a 360-degree turn.

Those bases are called G, C, A, and T, and the order they come in and their ability to form pairs with one another are huge. It’s how the cell interprets, copies, and stores genetic information. The discovery of this incredibly elegant structure made a huge splash, and pretty much invented the field of molecular genetics.

But, well... that’s not actually what our DNA looks like. At all, really. For one, if you stretched out all of our genetic material, or our genome, it’d be a little over a meter long -- per cell.

And most of us are less than a couple meters tall. So, in our bodies, things get packaged up a bit. DNA’s double helix is twisted up and bound by proteins to keep it neat and organized in the cell’s nucleus.

And then, whenever its genetic information is needed, other proteins pry it open and read it out. But also… the exact base-pair composition of a sequence of DNA can cause slight changes to its structure. Depending on what pairs you’re looking at, things can be straighter or more curved, for example.

So the B-DNA double helix is… more of an average. It’s close to what’s actually there. But there’s room for things to get real weird.

As we noted, one of the early X-ray crystallographers working on the structure of DNA was Rosalind Franklin. And well, she actually described two structures, which she found formed at different humidity levels. She named them A and B.

Watson and Crick’s model was based on the B form, and that turned out to be the default one in cells -- so, we’re stuck with B being first. But there’s room for A-DNA to shine, too. This is what you get when you take B-DNA and… kinda scrunch it down.

It’s shorter, and wider, but it’s still a right-handed double helix. For a while, we didn’t really know whether this structure would actually form in cells, as opposed to in labs with carefully controlled relative humidity and such. But it does look like A-DNA can show up in cells.

For one thing, this slightly-more-ungainly helix is what you get when you twist together a strand of DNA with its cousin RNA -- and it’s also the form of the RNA double helix, for that matter. But it can also happen in pure DNA. And in fact, this seems to help cells check their work when they’re replicating it.

The enzymes that replicate DNA are called polymerases. And when a polymerase is stringing together base pairs to make a new DNA strand, it doesn’t know what the sequence is supposed to be. But, say two base pairs are mismatched -- like, a T with a G instead of an A.

That makes a bit of a lump in the structure of the double helix. Specifically, in the minor groove. And the minor groove of A-DNA is a bit wider and more accessible than that of B-DNA.

So the lump is more obvious, and so is the mistake. When the polymerase spots that mistake, it can proofread its work by taking out the wrong base and putting in the right one. So, that turning B-DNA into A-DNA when a cell is dividing might help it avoid mistakes and potentially dangerous mutations!

So, we’ve established that B-DNA is right-handed, and so is A-DNA. And they’re always twisted the same direction. DNA can twist the other way, though -- it can be left-handed.

And… it looks kind of a mess. When the bases get flipped relative to their usual position,. DNA’s backbone gets all out of whack.

In fact, this left-handed form is called Z-DNA, because instead of making a nice smooth ribbon, the backbone zigzags. Yet this messy, backwards helix seems to serve an important purpose. See, when the cell needs to read or replicate a strand of DNA, it has to unwind the double helix to get at the base pairs.

And all that twist needs to go somewhere. Think about what it’s like trying to untwist two tangled cords. If the ends aren’t free to rotate, the twist just runs along down the line.

DNA has lots of enzymes to help keep its twist under control. But having the DNA itself twist the other direction also seems to help ease things up. And in fact, researchers have found that sites with the potential to form Z-DNA show up near the sites where proteins start reading many of our genes.

So it’s possible that this backwards helix has an important role in gene expression. Z-DNA may also help protect our genomes from Alu elements, a type of gene in primates that duplicates itself and jumps around from one place to another. What Alu does isn’t totally clear, but having things jumping around your genome can cause harmful mutations.

But some parts of the Alu sequence are capable of forming Z-DNA, and research has shown that our bodies have proteins that can bind to those regions and prevent them from spreading further. So we’ve got double helixes that can twist backwards. But who says it has to be a double helix?

Yeah, this is where things start to get wild. Welcome to H-

DNA: a three-, yes three-, stranded form of DNA. This is what happens when another strand of DNA binds to the major groove of an existing double helix. That can be a separate strand, or another part of the same strand doubling back on itself. And it, uh, seems like you really wouldn’t want this.

Case in point: In a 2004 study, researchers looked at a region that forms H-DNA in front of a gene called c-myc. And they found that this region was prone to mutations. Specifically, double-strand breaks.

This is exactly what it sounds like -- it’s when both strands of the DNA backbone snap. There are a couple of ways that adding a third strand to DNA might cause it to break. For one, DNA polymerase needs to be able to ride smoothly along a strand of DNA in order to copy it.

So if it runs into something weird, like a place that’s gone triple-stranded, it can screech to a halt -- and that’s been shown to cause double-strand breaks. Or it might happen when a well-intentioned DNA repair protein runs into a structure they know should not be there, and they try to fix it. Either way, when it comes to c-myc, this is bad news.

Because this is one of the most well-characterized cancer-causing genes out there. Genetic mutations in c-myc can cause cells to grow out of control. It’s also possible that H-DNA could be helping drive beneficial mutations.

But it’s clear that this is definitely something to pay attention to in the context of human health and disease. But wait, because we can still add more strands. I’m talking about four-stranded DNA.

You know how your shoelace has a little plastic piece at the end to keep it from unraveling and make it easier to lace up? That’s called an aglet, and chromosomes have those too -- though they are not quite for the same reason. They’re called telomeres, and they protect the ends of our chromosomes from damage.

Rather than just trailing off when the gene runs out, they have long stretches containing large amounts of the base guanine. And when four guanines line up just right, they can form a four-stranded structure: a G-quadruplex. Whenever a cell divides, these telomeres get a little shorter.

And when they get too short, well, the cell decides its time is up and enters programmed cell death. That’s a normal, healthy process: you don’t want cells to keep going if their genomes or integral machinery are old and damaged. So while there is a protein that can maintain telomere length, it’s mostly implicated in cancer.

And actually, G-quadruplexes help stop it from working -- so they maintain the overall health of your cells. That’s probably the best characterized function of G-quadruplexes, but these G-rich regions also exist in the interior of our chromosomes. And they have been implicated in preventing the turnover of the proteins that organize DNA, called histones.

The cell uses histones to make little notes to itself about when it might like to return to that sequence again. And when histones are recycled and new ones are brought in, those notes go away -- so G-quadruplexes seem to be involved in allowing a cell to pass its notes on when it divides. Those notes are a big deal, too.

They affect which genes get read and which ones don’t, and so long as they’re preserved, that controls how a cell behaves. Now, G-quadruplexes are one of the most well-understood kinds of four-stranded DNA, but there are actually way more forms of it. Like, that long string of guanines has a counterpart: a complementary strand of cytosines.

And those regions can make a four-stranded structure of their own, called an i-motif. Also, when DNA repair requires a cell to check the other chromosome copy to make sure it’s fixing things right, it creates an elaborate four-way structure called a Holliday junction. No one ever said genetics was simple.

But the incredible structural flexibility of DNA is something we’re still learning about, nearly 70 years after the discovery of the double helix. That structure shows us how DNA works, beyond simply encoding our genes -- which was already incredibly important. It turns out, this amazing molecule has a lot of tricks up its sleeves that help make life possible.

Thanks for watching this episode of SciShow, and thank you to all of our amazing patrons for helping make it possible. Patrons get access to neat perks, like our livestreams with members of our team, and a Discord where you can chat with us. If you’d like to become a member of our community, check out patreon.com/scishow. [♪ OUTRO].