DNA Structure & Replication: Our Instruction Manual for Existing: Crash Course Biology #33

DNA is the most useful instruction manual in the world. This special molecule contains all the information needed to not only make your body, but keep it running all your life. And DNA does this job in every living organism that we know of so far. But it's even wilder than that. Within those organisms are cells, trillions of cells in your case, that each need their own copy of the instruction manual. That's a lot of toner. And the manual is massive. If you were to print out the roughly 3 billion letters of the genetic code stored in your DNA, they would fill hundreds of thousands of pages. You've got the most robust technical library in the world inside of your body. Cells can read this manual cover to cover. But for nearly all of scientific history, we couldn't. Until 2022, when building on many decades of progress, scientists finally produced the first complete sequence of the human genome. That means that they were able to document, in order, the entire genetic code that makes a human body. This major breakthrough could help us understand all kinds of things. Like, what makes us similar to and distinct from other species? What makes some people respond differently to certain medications? And how can we treat diseases like cancer more effectively? Hi, I'm Dr. Sammy, your friendly neighborhood entomologist. And this is Crash Course Biology. Woof. So that was some pretty heavy stuff. Maybe some theme music could lighten the mood? So let's begin with what DNA is made of. Nucleotides, which are molecules that consist of three parts. A sugar molecule, a phosphate group made from bonded phosphorus and oxygen atoms, and one of four possible bases, which all contain nitrogen. We'll get more into these nucleotide bases in just a moment. But first, check this out. A bunch of these nucleotides link up in a conga line to form DNA's famous double helix shape. It looks kind of like a twisted ladder. The rails on either side are the sugar-phosphate backbones, named because they form the backbones of DNA, and they're made of chains of alternating sugar and phosphate molecules of the nucleotides. If you compared these two sugar-phosphate chains side by side, you'd see that the one on the left starts with the phosphate, and the one on the right starts with the sugar. It's like one chain is upside down. Biologists call these anti-parallel strands, and you'll see how this mismatch creates some shenanigans a little later. The rungs of this twisty funhouse ladder are formed by DNA's nucleotide bases, which connect to the sugars in the backbones. And when it comes to making DNA, your cells have four bases to choose from. The two largest are adenine and guanine, or A and G for short. The two smallest are thymine and cytosine, or T and C. In a healthy strand of DNA, a big base always connects with a small one, using weak chemical bonds called hydrogen bonds. To get even deeper, again, in a healthy strand of DNA, because of their structure, adenine always bonds with thymine, and guanine always bonds with cytosine. A common way to remember this pairing is, apples grow on trees, and cars go in the garage. So A goes with T, and C goes with G. Now here's where it gets really interesting. Your cells use these bases, A, T, C, and G, to store information. In fact, these four letters make up the whole alphabet of your genetic code. The specific order they fall into is what allows your DNA to make you a human, and not another animal like a chimpanzee. Throughout your DNA, these letters are repeated over and over again, in different combinations that form a message more than three billion bases long. Just four letters in countless combinations. All of this is packed up into chromosomes. Chromosomes are chains of DNA molecules that are coiled up tightly around special proteins that help them fit inside the nucleus, or control center, of each of your cells. And like I said at the top, almost every cell in your body has a complete version of this code. So that means that when you make new cells, and your body is always making new cells, they need a copy too. That's where DNA replication comes in. It's where the structure of DNA really shines. And all these details, the base pairs, the twisting ladder, they aren't random. They all fit together in a precise way that makes DNA replication possible. At the beginning of this process, an enzyme, or a substance that helps trigger a chemical reaction, splits the DNA ladder in half. It breaks the hydrogen bonds connecting the base pairs, and separates the two strands of DNA. Now get ready. Your cell's about to turn these half strands into two complete strands of DNA. And the amazing thing is, it already has all the instructions it needs, thanks to the specific order, or the code, of all of those base pairs. DNA replication is done mostly by an enzyme called DNA polymerase. And when DNA polymerase rolls up to a half strand of DNA, and sees a dangling adenine base, it knows exactly what to do. It needs to attach a thymine. Because remember, apples grow on trees. Then, if it sees a cytosine hanging out on that half strand, it knows to attach a guanine. Because cars go in garages. So to copy DNA, this enzyme travels up those half strands, and adds the missing bases, plus sugar phosphate backbones, to complete the structure. At the end of it all, boom! You have two full strands of DNA, ready to go into new cells. Each new piece of DNA has just one strand that's newly constructed, pulled together from nucleotides that were floating around inside your body. And a second strand that came directly from the old molecule. So DNA replication is considered semi-conservative, because the original strand of DNA is kept partially the same in the new molecule. And this is part of what makes DNA so useful. With just one strand, half a DNA molecule, cells have all the information they need to make more DNA molecules. For a closer look at how this works, let's head over to the Thought Bubble. When it's time for DNA replication, your cells don't unravel all of their coiled up DNA at once. If they did, you'd be left with a chain of material taller than I am. And I'm pretty tall, so... Okay, I'm not, but still. So instead, this process works in sections. First, an enzyme called helicase unravels a short stretch of DNA, creating a bubble in the double helix. This is a replication bubble, and each end is a replication fork. Once the bubble is open, DNA polymerase steps in. With one enzyme working on each unraveled strand. One polymerase moves along the DNA in the same direction as the helicase enzyme. This polymerase is working on the leading strand, which means its job is easy. Just attach complementary bases, A to T, C to G. Meanwhile, the other polymerase is going in the opposite direction, away from the helicase. It's working on the lagging strand, and its job is a bit harder. See, DNA polymerase is only able to add bases if it's moving forward. So the polymerase on the lagging strand ends up doing a bit of a weird dance. It's like it takes 5 steps forward, and then adds 5 bases, and then jogs backward 10 steps, and then it takes another 5 steps forward to fill in the gap, and then jogs backward 10 more steps. That way, it can add bases and short fragments as it moves forward. These fragments are eventually connected together into one continuous string, with the help of yet another enzyme. Thanks, Thought Bubble! Now, DNA replication works flawlessly almost all the time, which is really incredible when you think about it. Somewhere in your body, cells are dividing every second, and they almost always get a perfect copy of your genetic code. But every now and then, something does go wrong. For instance, DNA polymerase might attach a cytosine base to an adenine. It'll try to put a car in an apple, or grow an apple on a car, which really isn't going to work however you say it. In other cases, damage from the environment, like chemicals or a bad sunburn, might merge base pairs together, or even shift a big section of bases, really throwing a wrench in DNA replication. The good news is, your cells are generally on top of this. Enzymes keep close tabs on DNA replication, double-checking what bases are added, and making sure that the process is happening correctly. When working properly, if they run into a base that shouldn't be there, they'll fix it, and get that car out of the apple orchard and into the garage. Sometimes, though, these errors aren't caught, and they make it into the new DNA strands. From there, these errors can get passed on to future cells, or even to an organism's future offspring. When this happens, it's a mutation. They're not always as ominous as they sound, and they don't normally give you superpowers either. Some mutations can cause problems, including cancer, but other mutations are totally neutral. Like blue eyes in humans. That was caused by one mutation in a person who lived a few thousand years ago. Some mutations can even be helpful, like the one that lets many adult humans digest milk and cheese. It all depends on what parts of the genetic code get altered. In any case, every living thing, including you, acquires some number of mutations during their lives. But our bodies are always fighting against them, and usually they're pretty successful. In humans, DNA replication gets messed up about once in every 10,000 to 100,000 bases. And after your cells proofread their work, that rate goes down to 1 in 10 billion. So how do we know all this stuff? It's both too small for us to see without a microscope, and happening in too many billions of different cells for us to track all that action. Which is a huge part of what makes DNA replication so amazing. Many, many, many scientists have contributed, and are still contributing to our understanding of how DNA works. But today, we'll hang out with a particularly special pair in the theater of life. Dr. Tsuneko and Dr. Reiji Okazaki are Japanese molecular biologists. In the 1960s, they wanted to find out more about how exactly DNA replication happens. In one experiment, they added radioactive molecules to a bunch of thymine bases. They were basically hooking them up with tracking devices, they could follow the thymines as they were added into the DNA of an E. coli bacteria. The Okazakis and their team noticed that the thymines were being added to DNA in short bursts, only 1 to 2,000 base pairs long. Then those fragments were being strung together in a much longer chain. If this sounds familiar, it's because they were the first to observe what was happening on the lagging strand. At first, this process was so weird that other scientists weren't sure about the results. So the Okazakis kept on testing to prove to the scientific community that their data was right. Sadly, Reiji never got to see that recognition as he died of cancer in 1975. The cancer was likely caused by radiation from the nuclear bombing of Japan in World War II, which might have disrupted DNA replication in his own cells. In 1978, Tsuneko and her colleagues presented enough data to validate her and Reiji's work for good. And those short segments of DNA on the lagging strand have been recognized as Okazaki fragments ever since. The structure of DNA is one of the big reasons that life on Earth has gone so well. With only a four-letter alphabet, DNA contains all the information it takes to make your body or in other cases to make a mushroom, a bacterium, or a dolphin. And all things considered, that code is fairly straightforward to read and duplicate because certain bases always match up and your body only needs half a strand of DNA to make a new, complete copy. For as complex as life is, some things about DNA are surprisingly simple. Of course, just having a giant instruction manual in your cells isn't enough to get your body to work. Next time, we'll learn how cells translate that manual into short, easy-to-follow instructions that keep life on Earth going. Peace! This series was produced in collaboration with HHMI BioInteractive. If you're an educator, visit biointeractive.org slash crashcourse for classroom resources and professional development related to the topics covered in this course. Thanks for watching this episode of Crash Course Biology, which was filmed at our studio in Indianapolis, Indiana, and was made with the help of all of these nice people. 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