The Science of Everything Podcast - Episode 44: Cell Division

Episode Date: January 12, 2013

A discussion of the cell cycle and cell division, beginning with an overview of chromosomes and chromosome structure, and then proceeding through a detailed discussion of the G1, S, and G2 stages of interphase, and the prophase, prometaphase, metaphase, anaphase, telophase and cytokinesis phases of M-phase. I conclude the episode with a discussion of cell-cycle regulation, including the role of cyclin-dependent kinases, cell checkpoints, and growth factors. Recommended prerequisites are Episode 10: The Cell, Episode 18: Biochemistry Basics, and Episodes 34 and 35: DNA Structure and Function.

You're listening to The Science of Everything podcast, episode 44. Cell Division, and I'm your host, James Fodor. So in this episode, we're going to talk about cell division. In particular, we're going to talk about the cell cycle and the different phases in that, including interphase, synthesis, and mitosis. We'll go through all the different phases of mitosis, prophase, prophase, perephase, metaphase, and telephase. We'll look at cytokinesis, and then we'll talk about some of the mechanisms of

by which cells regulate the cell cycle, including cyclone-dependent kinases, the cell checkpoints and also the role of growth factors. Recommended pre-listening for this episode include episode 10, The Cell, Episode 18, Biochemistry Basics, and Recommended is also episodes 34 and 35 about DNA structure and function, although that's not as crucial, but it would be useful if you had that background. Let's get on to the episode. First of all, just a short word on the structure of chromosomes.

Again, this is where the previous knowledge about DNA structure and function would come in handy, because you'll understand more of the terms I'm using, but not essential. So chromosomes are composed of chromatin, which is a complex of DNA, about 60% and about 40% proteins, so it's DNA and protein, sort of combined together. Each chromosome is a single continuous double strand of DNA, usually around like 150 million base pairs along, although it differs a lot between the different chromosomes and humans. But we're talking, you know, hundreds of millions of base pairs, so it's pretty long. It's double-stranded, so you know the DNA is the double helix with the two strands bonded to each other, so there are a...

two actual individual strands of DNA on the chromosome. But when people normally think about chromosomes, they think of these sort of roughly X-shaped structures. That's often what is displayed with the caption of chromosomes in books and websites and so on. Those are chromosomes, but those pictures are a bit misleading because chromosomes only look like that just prior to mitosis, or when the chromosomes have condensed and also the DNA molecules have already been replicated during the synthesis phase. We'll talk about this in more detail, but the point that I want to make is chromosomes don't usually look like that. Usually they just basically one single long strand, so more like the letter I rather than the letter X, because usually there's only one copy of the DNA

in the nucleus, not two copies, which is the case in when they're in that X form. And usually the chromosomes are not condensed like that. Usually they're much more dispersed throughout the nucleus. So, yeah, when you think chromosomes, don't think those X structures think more amorphous, big long strands of chromatin that it's all tangled up inside the nucleus. The other thing people usually think about when they think of DNA is the actual double helix structure, which is DNA, but that's only what DNA looks like at the sort of very smallest level. DNA in, that's contained in the nucleus, is highly structured and bound in various forms. So at the most basic level, those DNA double helix strands are wound around circular proteins called histones, which are in

turns that are bunched up together, so the histones and the DNA that winds around them are bunched up into much thicker fibers that are called solenoids or chromatin fibers. And these fibers in turn are bunched up and wound around in sort of wavy structures and have more proteins attaching to them for structure as well that are pushed together inside the nucleus and form the chromosome. So normally when, you know, during like the G1 phase, and again we'll talk about this in a moment, but, you know, during phases of the cell cycle other than mitosis and immediately prior to mitosis, the DNA is not found in very tightly formed chromosomes. It's, it's the DNA still wandered around the histones and a bunch together into chromatin fibers and so on.

So it's still compact, but it's not as compact as it is just prior to mitosis when it all really clumps together into those X structures. Just to summarize what I've said in this first part, the chromosome is the single long molecule of DNA and the proteins that bind to it. It is not essential that it be in that X-shaped structure that most people think about. Okay, onto the cell cycle. The cell cycle consists of five phases, but really, It's divided up into three sort of main groups of phases, and then those are sort of subdivided.

So the way I'm going to divide it up is between interphase, mitosis, and cytokinesis. So interphase is the main period of the life of the cell, when the cell is just doing its thing and not dividing. Mitosis is the period when the sister chromatids are separated into the two separate nucleus. So basically you go from one nucleus to two nucleus, each with its own copy of the DNA and the chromosomes. cytokinesis is the period of actual cell division where basically the cytoplasm is snipped in half one nucleus inside each of the now daughter cells. So cytokinesis comes just after mitosis. It's the period where the cells actually divide. Mitosis is just when all of the preparations to division take place, especially the separating of the cysticromatids.

Now, cytokinesis basically just sits on its own. It's just cytokinesis, the cell, the mother cells splits up into two daughter cells and that's it. But interphase and mitosis are themselves divided up in sub-phases. Interphases divided up between G1, S, and G2 phases. We'll talk about those more in a moment. Mitosis is divided up into five sub-phases called pro-phase, pro-metaphase, metapphase, anap phase, and telephase. And we'll go through each of those in order later on. But just to keep in mind that mitosis has its own subsections. Most of what we're going to be talking about in this episode are the phases of mitosis, but the cell cycle itself includes the phases other than mitosis, that is interphase and cytokinesis. Now,

The time taken for a complete cell cycle varies a lot between different organisms and also different cells within the organisms and the time in the lifespan of the organism and many other factors. So one of the shortest ones is fruit fly embryos which take a minimum of eight minutes for the complete cell cycle. That's not just mitosis, that's the whole thing. Human liver cells, on the other hand, take an entire year to go through the cell cycle. Many cells you can think about as dividing like once a day or something like that, so an order of days. but as you've seen from 8 minutes to a year, it varies a very large amount. Now, the actual phase of mitosis itself only takes maybe an hour in many human cells. The rest of the time is taken up by interphase, which can vary greatly in length.

Now, interphase, remember I've said, is divided up into the subsections of G1, S, and G2 phases, but there's also another one, which is sort of like an optional phase called the G0 phase. This is essentially a static phase. So G essentially stands for growth, the growth phase, and there's G1 and G2 phases. They're not really that different except for the fact that they're essentially. separated by the S phase, synthesis phase, which is when the DNA replicates. But there's another one called G0, which the cell can potentially enter, where it's the static phase. The cell is not growing. Some cells like muscle and nerve cells remain there permanently. So particularly

neurons are often in the G0 phase, which is why people, which is why there has been a belief that, you know, neurons don't divide. You can't grow new neurons. This is now known not to be strictly true. There is examples of neurogenesis, even in adult human brains, but it's still all, you know, sort of the exception rather than the rule. So, for the most part, neurons and certain other cells in humans are permanently in the G-Zero phase, which means that, you know, they make proteins and express genes and so on, but they're not growing and they're not synthesizing new. They're not replicating their genomes and they're not dividing. Most cells spend about 90% of their life or their time in interphase, which is the G1, S, and G2 phases. So I'm now going to talk about

each of those phases in turn. So the G1 and the G2 are gap phases, or growth. phases, meaning that the cell continues to grow, it synthesizes proteins, but nothing much happens in terms of cell division. The key difference, by the way, between G0 and G1 and G2, is that in G1 and G2, this cell continues to grow, so that, you know, it incorporates new material, it may replicate new organelles. Its cytoplasm physically increases in size, that sort of thing. That doesn't happen in G0, but in all of those G-phases, protein synthesis and gene expression will still occur because, you know, the cell has to do its thing. It has to, you know, function in some sense and protein synthesis and activation is the way that cells function. Okay, so in between G1 or G2

is the S phase or the synthesis phase. Now this is called the synthesis phase because it's the time during which the cell DNA is replicated. So during G1 phase, which precedes the S phase, the cell only has a single copy of its genome. All of the chromosomes, they're still double-stranded, of course, but that doesn't, the two strands don't count of different copies. They're just sort of the positive and negative versions, if you like, of the sense and the anti-sense versions of that chromosome and the genes on the chromosome. But during the synthesis phase, the DNA is replicated, so they're now two distinct copies. These two copies of the DNA are called cister chromatids, cister, because, well, you know, they're identical, essentially. And they are also connected to each other

by a sort of central bulge or constriction, which is called the centromere. So this is the extract that they're talking about. The middle of the extrustructure has a sort of a bulge. That's the centromeremia. That's where a bunch of proteins are connecting the two cister chromatids. Now, I did a fair bit of reading and research on this, and it seems to be that the word chromosome is actually used somewhat inconsistently. It refers both to the individual strands of DNA plus proteins and also to the entire complex, so both cysticromatids plus centromere. So that is, when you say chromosome, it could be referring to either one of the arms of the

X structure or both of the arms of the X structure plus centromere. The way I'll refer to it to avoid ambiguity from now on is the chromosome will refer to the entire X structure, and a chromatid will be one side of that. So there are two chromatids or sister chromatids in the chromosome connected at the centrum here, and each sister chromatid has an identical copy of the DNA of its alternate sister chromatid. During the S phase, the DNA from each chromosome is replicated, thereby forming this chromosome structure with sister chromatid. In it before that, there's only one copy of each chromosome. Afterwards, there are two connected at the Centromere. So, again, the key thing that happens during the S or synthesis phase is that the DNA is replicated. Before that, during the G1 phase, there's only one copy of the DNA.

Afterwards, during the G2 phase, there are two copies of the DNA connected together at the Centromere. However, although the two-sister chromatids will be connected at the Centromere during the G2 phase, they are still not coiled up into those famous X structures until right before mitosis begins. So before we get into the details of mitosis, there's one final concept that we need to talk about, which is very important, and this is a structure within the cell, which is called the mitotic spindle, or sometimes the spindle apparatus. So the spindle apparatus is a complex of proteins that physically pulls apart the two cysticromatids during mitosis. How it does that, we'll get into more detail later on, but for the moment we just need to understand what it is and the various components

that make up the spindle apparatus. So there are three months. main elements to the spindle apparatus. The spindle microtubules, the proteins that are associated with the microtubules and help with the attachments and so on. We won't really talk about those too much. And the third element, the centrosomes. So let's look at each of those in turn. Microtubules are a key component of the cytoskeleton, which you would remember from our episode about the different structures within a cell. Microtubules are basically comprised of hollow cylindrical polymers of tubulin monomers, so that tubulin is just a protein. combine monomers of that together, you get polymers which form hollow cylinders.

You sort of put a bunch of those together and they form microtubules. They're just big long structures that basically form the skeletal backbone of the cell. You could sort of think of them as the underlying structural framework upon which the cytoplasm and the rest of the cellular organelles are allayed. So the microtubules form the cytoskeletal, which keeps the cell together. but they also form another important task in mitosis, which is that they've formed the basically, think of them as sort of ropes,

that attach to the cysticromatids and also the centrosomes and physically pull apart the cysticromatids thereby splitting the X chromosomes into two. So that's what the microtubules are. The centrosomes are organelles that basically serve as the main organising center of the microtubules.

Many of the microtubules that play a role in mitosis are connected to, the centrosome. So you can think of the microtubules as sort of like spidery legs that extend outwards from the centre, which is the centrosome. Each centrosome, there are two in a cell undergoing mitosis, is comprised of a bunch of proteins, as always, that play structural and other functional roles. But crucially, two cylinder shaped collections of microtubules called centrioles. These help stabilize and organize the microtubules. We won't go too much into the detailed structure of these centrioles or how they are comprised, how they comprise the centralisome,

because it's not really that important. But basically, just imagine a bunch of microtubules arrayed in a sort of a cylindrical pattern. So remember, the microtubule itself is a hollow cylinder. So basically put those cylinders in another cylinder, and that cylinder of cylinders is basically a centriol. You get two of those, which are sort of oriented in a certain relation to each other and some other proteins, and that complex forms the centrosome. And there are two of those, basically one on either side of all of the chromosomes. And we'll get into that in more detail later, but we just need to know what a centrozone is. So during interphase, especially during the S and importantly the G2 phases, the initial two centrioles that form the original centrosome

move apart and then duplicate. So remember, there are two centrioles that are sort of oriented at 90 degrees to each other. So if you can think about it, one sort of lying down and one standing up in a sort of a simplistic sense, these two move apart during the G2 phase. And each other, you of them replicates. So now instead of two centrioles forming one centrosome, there's now four centrioles forming two centrosomes. And these two separate centrosomes then move apart as well, and they form a crucial part of the spindle apparatus, which, as we know, pulls the cysticromat apartis apart during mitosis. The mitotic spindle or spindle apparatus as a whole is sort of roughly ill-ozoidal in shape. It's got two poles. These are called the mitotic poles. One centrosome

is at each of the poles. And remember, the centrosomes are the main organosos are the main organ organising centres for the microtubules. So the mitotic spindle as a whole is basically comprised of an ellipsoid shape with one centrosome at each end and a bunch of microtubules protruding inwards, and some outwards, but mostly inwards from the centrosomes. So you can sort of think of it as if you've got the centrosomes on either side and they're sort of reaching inwards with their microtubial arms towards each other. We'll go into some more details about the structure and function of that as we go through the stages of mitosis. But that's basically what the mitotic spindle is. To summarize again, it's centrosomes with microtubial arms protruding in towards each other and various associated proteins. Okay, so that's enough preliminary information about chromosomes and the different phases of the cell cycle and the mitotic spindle. Now let's get into the meat of the matter and talk about mitosis itself. So remember, mitosis only occurs after the interphase, after G1 phase, after synthesis when the DNA is replicated, and after G2 phase when the centrosomes are replicated and when the cell has grown sufficiently in order for, it to be ready for cell the vision proper.

After the interphase is completed, G1, S, and G2, we move into what's called M phase. M phase is just mitosis plus cytokinesis. So we're now going to talk about M phase, starting with mitosis, which is the main part where the chromosomes are pulled apart. And cytokinesis remember is when the cell physically divides. So, mitosis, as we said before, is comprised of five subphases, prophase, prophase, Prometaphase, metaphase, anaphaease, and telophase. And these can be a little bit hard to remember,

but I'll try and make it a little bit easier by sort of basically translating from, I think Greek is where these names come from. Prophase basically means the before phase. So that's useful because it happens first, and so it happens before or the other phases. Prometaphase comes after pro phase, and it basically means before the after phase.

And metaphase means the after phase. So you basically got the before phase, the after phase, and between them, the before the after phase. Prometaphase is sometimes just sort of subsumed under metapaze, which is why it's got sort of a weird name. So the first three phases again, pro phase, pro-metaphase, meta phase, before phase, before the after phase, and the after phase. Then the final two phase is anaphase and tiller phase means the telophase, and tillapase means the end phase. So telophase is pretty easy to remember end phase. Anap phase is a little bit weird, but it happens near the end,

so it's sort of like a repetition of things that have gone before. I mean, it isn't really, but that's sort of how you can remember the name. Anyway, so beginning with the prophase. Prophase begins when the chromosomes first become visible under a light microscope, as they have now condensed enough to be seen, forming the classical X-shaped pattern that we're used to. Now, remember before, I said that when people normally talk about chromosomes, they're thinking of those X-shaped chromosome patterns.

Each of those X-shaped chromosomes is actually comprised of two sister chromatids and has two distinct copies of the DNA. normally during most of the phases of the cell cycle, the chromosomes are only a single strand of DNA plus proteins, and they don't form that X structure, and also they're usually not visible in such a condensed form, because normally they're much more dispersed throughout the nucleus. But just before, you know, during the final phases of G2, leading up to the beginning of mitosis, the chromosomes begin to condense. They've already been replicated, so they're already two cysticromatids joined by Centromeremia,

but now they're beginning to condense. Once we can see these X-shaped structures under... the light microscope, then we say that prophase has begun. At the same time, remember we've got our two centrosomes comprised of the centriole pairs. These have already been replicated during the G2 phase. At the beginning of prophase, they also separate from each other and move to opposite ends of the cell, and this is crucial for later on. Once the two centrosomes have moved to opposite ends of the cell, they begin to form the mitotic spindle, or the spindle apparatus. Basically, remember the spindle apparatus is centrosomes, we've already got those, plus the microtubes

that are extending inwards, one from each central zone, or one segment of the microtubules coming from each centrosome. There are many microtubules from each centralisome. These begin to grow and extend by polymerization of the protein monomers during prophase. So that's another important thing that happens during prophase. As the spindlele apparatus is forming, the nuclear envelope breaks down. So the nuclear envelope is just the membrane that surrounds the nucleus during interphase, but during prophase it breaks down, and this sort of allows the microtubules to extend right from the, right from the centrosomes, to actually reach the chromosomes. Because if the nuclei membrane was there, that there'd sort of be a barrier preventing the

microtubules from accessing the chromosomes, which is crucial. So the nuclei membrane has to break down in order for the microtubils to gain access. So to summarize, key things that happen during prophase, chromosomes become visible because they've condensed down. Centrosomes move to opposite ends of the cell and begin to extend their microtubules into the center, and the nuclear membrane breaks down, allowing the microtubules to gain access to the chromosomes. Now, moving on to the next phase, Prometaphase. Prometaphase begins just when the nuclear membrane finishes breaking apart. And by the way, this is catalyzed by various enzymes that help to break down the lipid membrane,

but the details of that aren't really important. We're just trying to get an overview of what's happening here. During Prometaphase, this is basically the subphase of mitosis when the spindle apparatus really sets itself up properly. Now, remember I said that the spindle laparitis is composed of the centrosomes plus associated proteins plus the microtubules. Well, there are actually three different types of microtubules. I mean, they're not really different.

They're the same stuff, but they're used for different things, and they form different components of the spindle laparitis. So it's important to distinguish these. The first type are what are called the connector core microtubules. These are the microtubules that extend from the centrosome inwards towards the chromosome and actually physically attach to a sort of a protein complex located at the centrosome, so at the centromere, so remember the centromere is the sort of bulge in the X-Tex-chrome

where the two cistercromatids are connected. At the centromere, each cistercromat has a protein complex, a protein complex called the connector core, and the connector core microtubules extend from the centrosome to each cistercromatins connector and connect to it, bind to it. These connector core microtubules, extending again from the centrosome to the connector of each cisterchromatid, are crucial for actually physically pulling apart the cister chromatids. Connector core microtubules, that's one type of microtubules that comprise the spindle apparatus.

The second type are called the overlap microtubules, and they are so called because they extend from each of the centrosomes onwards towards the chromosomes, but unlike the connector core microtubules, they do not actually touch the chromosomes, but rather they sort of move past the chromosomes and actually extend and interdigiate with the overlap microtubules from the other centrosome. So interdigiate basically just means if you hold your hands out from, out of you front of you, palm towards you and fingers separated and move your hands in towards each other, your fingers push in between the gaps between the fingers of your opposing hand, and that's called basically you're interdigiating your fingers. That's exactly what happens with the

overlap microtubules from, except instead of obviously emerging from the hands, they emerge from the microchubules emerge from the centrosomes, one located on either side of the cell. Some bonds are formed between the microchubules that are overlapping, so that would be like bonds forming between your fingers, and that helps to stabilize the spedalopritis. The third type of microtubules extend outwards from the centrosome, but instead of extending towards the chromosomes, they actually extend in the opposite direction, sort of out towards the cell membrane. They're not crucial for mitosis, but they do help to stabilize the mitotic spindle.

And so I just thought I'd mention them. these are the astral microtubules, because they're pointing away from some of the main structure. This intricate network of microtubules, where we've got the connecticore microtubules connecting to the chromosomes themselves, the overlap microtubules overlapping with each other and interdegiating, and then the astral microtubules pointing away helping to stabilize the whole thing, that complex structure really takes shape during prometaphase, and particularly we define pro metapase as the period when the connecticore microtubules actually make contact with and bind to the connecticle regions on the centromere of each of the chromosomes.

Any failure of connection of these connecticore macrotubules is catastrophic, basically, because it will lead to mistakes in cell division. If only one of the centrosomes successfully connects to a given chromosome, then that means that, and the other centrosome doesn't, then that means that that given chromosome is only going to be pulled in one direction, say, to the right, not in the left. Usually the idea is that each chromosome is, are pulled in both directions, both left and right, by the centrosomes on the corresponding

signs of the cell. Being pulled in both directions allows the sister chromaties to be pulled apart, and therefore each side of the mother cell gets one of the sister chromases, and therefore one copy of the DNA. But if one of the connections fails and, say, a given chromosome is only connected to the right-hand centrosome, but not the left-hand one, then all the force comes to pulling that given chromatid to the right, the right-hand daughter-cell will get two copies of that chromosome and the left-hand one will get numb. And so that can be very problematic and lead to various diseases or syndromes, which can happen when people get multiple copies of a given chromosome or no copies of a given chromosome. Or often, that can lead to

very serious complications. So, that's what happens in pro-metaphase. Now moving on to metaphase, or again the afterphase. Metaphase begins as the chromosomes align at the center of the cell in a semicircular relationship. This alignment, basically in the middle of the cell, is due to the counterbalance of pulling forces, generated by the centrosomes on either side of the cell. Remember, the centrosomes are still sort of moving apart from each other. They've got their connected core microtubules, which are connected to all of the chromosomes,

and therefore each of the centrosomes is trying to pull all of the chromosomes towards itself. So there's sort of a tug of war going on between the two centrosomes, trying to pull to the left and pull to the right. As this happens, the balance of forces between these, the two centrosomes should basically align all of the chromosomes at the center of the cell. So they've all been condensed, that's happened, that's start of prophase, but now they're all lining up at the center of the cell. So if you sort of looked at the cell top down in a sense, like if it was on a petri, you just

or something, you'd basically see on the left, there's a centrosome. It's extending microtubules inwards, which connect to the chromosomes, which are now aligned at the middle of the cell, and then to the right, we've also got our connected cores coming from the right-hand centrosome, which is on the right side of the cell. This phase is crucial when, because the cell will not proceed to anaphase until all of the chromosomes are properly aligned at the center of the cell and until all of the connector microtubules are properly connected to their corresponding connector core, so that every chromosome is properly attached to both the left and the right centrosomes. It's not fully understood

exactly how the cell knows that this has occurred, but it's thought that unattached or improperly connected connector's, or improperly located chromosomes may generate some kind of signal that prevents the premature progression to anaphase, even if most of the connector calls have been attached. and most of the chromosomes are aligned, still not good enough. All of them have to be properly aligned, and again, that's crucial, because if each daughter cell needs a full copy of the genome, and therefore they need a copy of every one of the chromosomes, and two copies can cause problems and no copies can also cause problems,

so it needs to be properly connected. Exactly the nature of these signaling molecules is, as far as I'm aware, not fully understood. We now enter anaphase, or the again phase, when we've got the chromosomes all aligned, sort of in a semicircular pattern at the center of the cell, and all properly connected to each of the two centrosomes on the left and the right via the connecticor microtubules.

Anaphase, in a sense, represents the climax of mitosis, because this is when the two cysticromaties are physically pulled apart. They're actually separated during anaphae. Everything that we've gone through so far, prophase, prophase, and metaphase have all been leading up to this point when we can actually separate the cysticromatids. So this separation happens as the centrosomes continue to move apart from each other, as a cell sort of elongates and the central chromosomes move towards the opposite ends of the cell, and the connector-microtubules pull, being connected to each of the central chromosomes,

pull on the chromosomes from each direction. So there are several mechanisms that contribute to the cysticromatids being physically separated. First of all, the connecticore microtubules shorten as a result of depolymerization. So basically special proteins go about depolymerizing or ripping out monomers from the connecticor proteins, thereby shortening them, thereby essentially exerting a force that is pulling the chromosome in each of the directions, towards the two poles, towards the centrosomes. The second mechanism is that the overlap microtubules lengthened by polymerization. So just as the connecticle microtubules are being depolymerized and shortening, the overlap microtubules are being lengthened by polymerization, and that continues to push the poles apart. Remember, the overlap microtubules are the ones that are interdigating and sort of connecting to each other in the middle.

If these lengthen, that essentially is going to push apart the two centrosomes. Now, that wouldn't necessarily lead to anything interesting if the connecticle microtubules also lengthened, because basically if you think about it, if the distance between the two centrosomes increased, but the length of the connecticle microtubules also increased, then the situation would just be the same, except with the size of the cell basically being increased.

However, this is not what happens. What happens is the overlap microtubules lengthened by polymerization, the centrosomes continue to move apart, and the connecticle microtubules shorten. So a combination of these processes leads to the cysticromatids being pulled apart by forces acting in both directions. The third mechanism is that the astromicotubules

are pulled by motor proteins attached to the cell membrane, thereby pulling the two spindle poles apart, or the two centrosomes apart. So basically we can summarize anaphase by saying that anaphase is the subphase of mitosis during which the cysticromatids of the chromosomes, now aligned at the center of the cell, are physically separated from each other.

This occurs as a result of the two centrosomes moving further apart from each other and as a result of the connected core microtubules connecting the centrosomes to the two cysticromatis shortening. The connecticore microtubules shorten because of depolymerization and the centrosomes continue to move apart from each other because of two factors, the astral microtubules pulling

because they're connected to the cell membrane. So the astro microtubules pull sort of from the outside and from the inside, the overlap microtubules. lengthened by polymerization, thereby sort of pushing the central chromosomes apart. So central chromosomes are both pushed by the overlap microtubules and pulled by the astromycopul tubules, as there's also both of those factors, the centrosomes move further apart, thereby pulling on the connecticor microtubules, which in turn pull on the two cysticromatids, and this pulling force is sort of magnified by the fact that the connecticor macotubors are also

shortening, so therefore increasing the pulling force. And eventually that pulling force is sufficient to physically separate the two cystic chromatids, thereby sort of ripping them apart at the centromere where, remember, they were previously attached to each other. After the climax of anaphase, we've just got telophase, or the end phase, to finish off. This final phase is marked by the reappearance of the nuclear membrane, now around each of the two daughter nuclei. So remember, once the cysticromicis have been pulled apart, we've got two sort of distinct groups of chromosomes. The chromosomes now are no longer in that X format, because

they've been ripped apart, so they sort of look like eyes, or sort of a little bit bent eyes, because you can imagine cutting an X in half down the middle, that's sort of what the two are cysticromatitis look like after they've been separated during anaphase. These two groups of cysticromatids will have nuclear membranes formed around them again, this is called the daughter nuclei, during tillophase. And shortly after that, the chromosomes will disappear as they decondense. So before mitosis, what happens is that the chromosomes are first replicated, and then they condense, and so we can see them, and then they align at the center of the cell.

Then we sort of have a reversal of those processes. First, during anaphase, the chromosomes are pulled apart as the cysticromatids are separated, then we get the reformation of the nuclear membrane around that, around each of the two groups of daughter nuclei, and then the daughter nuclei decondense and therefore return to their more amorphous state. So that leads us on to the final section of M phase, which is cytokinesis. So telephase ends basically as the nucleam membrane is appearing around the two sets of daughter nuclei and as the chromosomes are decondensing. But around the same time, cytokinesis actually begins.

So cytokinesis and telephase are basically occur more or less at the same time, while they overlap, but they are distinct processes, and so we sort of separate them out. Cytokinesis is basically just the physical separation of the cell into two. The cytoplasm is basically, I mean, is literally snipped into two essentially, so that now each of the two daughter cells has a set of a full set of genetic material, mitosis is taken care of that, and the other organelles will also be distributed, basically, between the two daughter nuclei. each daughter nuclear will also have one centrosome as well, because remember, there was one of those

each opposite side of the cell, and once the cell divides, each of the daughter cells will pick up one of those centrosomes. Basically, the manner in which cytokinesis occurs is that a band of actin filaments, which is just a type of microtubule, basically, forms around the center of the original cell and slowly constricts. So it sort of forms a, what's called a cleavage burrow that gradually deepens and deepens, thus cleaving the cell into two until finally the two sides split apart. and the organelles are distributed haphazardly, as I said before, between the two daughter cells. As long as each daughter cell contains at least one copy of all of the different organelles,

then it's not really a problem because they can be replicated as needed. So as long as each of the daughter cells has, you know, at least one ribosome and at least one vacuole and stuff like that, and at least one mitochondria, you know, they'll be fine because they can be replicated as needed. And once the cell has split in two, the organelles have been distributed and the DNA has decondensed, then cytokinesis is complete, M phase is complete, and basically we enter again either the G1 phase or the G0 phase. Usually the G1 phase would happen at least for a while because the cell needs to, in a sense, build up its strength after it's just been formed and it needs to grow a bit and generate some

energy reserves or build up energy reserves and probably replicate some of its organelles and stuff like that. But once the M phase is finished, the cell will end to G1 phase and then perhaps it will end to G0 phase where it stops growing or it'll move on then after a certain amount of time to S phase where it will synthesize. a new lot of a new copy of its DNA, perpetrator to entering yet another sequence of mitosis and cytokinesis. And so, sort of the cycle of life continues, if you like. So that's the basics of the process of mitosis and cell division itself. In the final part of the episode, we're just going to

spend a bit of time talking about how the cell cycle is regulated and some of the key. So the first of these that we'll talk about are cyclin-dependent kinases or CDKs. So cyclone-dependent kinases are just kinases that are dependent on cycling in order to operate. So what does any of that mean? A kinase is a type of enzyme that operates by transferring phosphate groups from high-energy donor molecules, like for example ATP, which is basically the main energy source of cells, to other molecules or substrate molecules in a process called as phosphorylation. Why any of that's important is because basically by transferring phosphate groups from high-energy molecules to relatively lower energy protein molecules or other molecules, kinases activate those protein molecules.

Basically, it changed their confirmation in such a way that they do something interesting that performs some sort of necessary function for the cell. So kinases are an important type of protein that basically help in activating other proteins, and so stuff happens. Cyclone-dependent kinases are a particular family of kinases that were first discovered because of their role in regulating the cell cycle. I don't think that's the only thing they do, but that's sort of the main thing we're interested in. CDKs are relatively small proteins, but the crucial thing about them is that they must be

bound to an additional regulatory protein called cyclin in order to be activated. So basically, kinases are proteins that activate other proteins, but cyclin-dependent kinases, in order to fulfill their function of activating other proteins, in turn, need to be activated themselves. So it's like activation by cyclin, then activation by kinase. And then the final protein actually does its thing. So it's sort of a two-stage process. Kinase is just another type of small protein.

Sorry, cyclin is just another type of small protein. So cyclin activates the cyclone-dependent kinase, which then activates the other process. And this cyclonect kinases help to regulate the cell cycle because basically the concentration of cycling varies across the cell cycle. It basically depends upon how much of it has been created as a result of expression of those particular genes that code for the cycling and related proteins. Concentrations of cyclin vary over the course of the cell cycle just providing one means of controlling progression from one state to the next because the cyclone-dependent kinases

won't be active in large enough quantities until you've got enough cycling. and if the cyclone-dependent kinases are not active in sufficient quantities, then all of the other proteins that are necessary for, say, forming the microtubules and replicating the DNA and all of those other things, all of that's done by proteins, and those proteins must first be activated by the cyclin-dependent kinases. If the cyclone-dependent kinases are inactivated because there's not enough cycling, then the whole process doesn't get off the ground. So presence or absence of sufficient concentrations of cycling

can be one mechanism by which the cell regulates its progression through the different phases of interphase, you know, G1, S, and G2, and also mitosis. There are many other regulatory genes and proteins that are relevant as well, so it's not just cyclone-dependent kinases, but they seem to play a very important overarching role. The concentration of cyclin over the course of mitosis is sort of cyclical, so it gradually increases up to around anaphase and then decreases dramatically as cyclin is broken down, so thereby returning to early levels and sort of preventing the cell from divining again. So as cyclin builds, more and more of these proteins,

routines are activated and therefore cell cycle commences and continues, but as that occurs, cycling is broken down and cycling concentrations decrease, and therefore the cell will not be ready to undergo cell division again or enter the new, enter mitosis again, until cyclone levels have been built up once again. So that's sort of how cyclone-dependent kinases play a crucial role in regulating the cell cycle and mitosis. And you'll hear about it quite a bit because I think only about 10 years ago the Nobel Prize was awarded for the discovery of these things. of these things, and there are a very large active area of research in biochemistry, molecular biology at the moment, so it's useful to know a bit about them.

Another mechanism that's used by the cell to regulate the cell cycle are what's called cell checkpoints, and these are pretty much exactly what they sound like. They're checkpoints such that at each of these checkpoints, the cell checks to see if it's met certain prerequisites, and if it has, then only then will it move on to the next stage. If not, it is stopped, and the cell remains in its given stage until those pre-recrucure. prerequisites are met and therefore it can pass the checkpoint. There's three main checkpoints that we know about, the G1 checkpoint, the G2 checkpoint, and the spindle checkpoint. The G1 checkpoint is the first checkpoint. It's located at the end of the G1 phase, as you might have thought by the name. It makes sure,

its role is basically to make sure that the cell is ready before it replicates its geno, because remember that's what occurs during S phase. The DNA is replicated. The cell will only proceed from G1 to S phase, if it has sufficient nutrition and if external cells are promoting growth and division in the proper way. My understanding is that the full details of exactly how the checkpoints work are still not fully understood. However, it's thought that the checkpoints are maintained by basically a complex network of activation proteins and also signals from other cells, so that is proteins bind to the cell membrane, which then leads to other proteins activating, which then activates other proteins, and that in turn leads to gene expression and other things like that.

This sort of complex interaction of protein networks and protein activations and so on, both internal to the cell and external, receiving signals from neighboring cells, is responsible for making sure that the cell will not replicate its genome until it has sufficient nutrition, that is until the G1 checkpoint is met. The second checkpoint is called the G2 checkpoint, and it's located, as you might have guessed, at the end of the G2 phase, just before M phase. So, whereas the G1 checkpoint makes sure that the cell is ready to replicate its DNA, the G2 checkpoint make sure that the cell is ready to actually undergo mitosis.

Basically, what the G2 checkpoint does is make sure that the DNA replication was completed successfully. If not, the cell clearly isn't ready to divide because you need two full copies of the genome for that to happen. The final checkpoint that we'll talk about is the spindle checkpoint, which occurs during metaphase. So this is like halfway through mitosis. It occurs at the point where all of the chromosomes should have been aligned along the central axis of the cell, which is called the mitotic plate, and also be under bipolar tension, which means that each of the chromosomes should have been attached to

by connected core microtubules protruding from each of the two centrosomes. So basically, the spindle checkpoint ensures both that the chromosomes are all in the right position and that each chromosome is attached to both of the central chromosomes. Remember that if this hasn't occurred, then there'll be problems because one of the daughter cells won't get any copies of a given chromosome and the other daughter cell will get two copies, and that's bad. So the spindle checkpoint is designed to make sure that doesn't happen. So as I said before, these checkpoints operate by a complex interaction of genetic and protein

interaction networks, which are still not fully understood. However, they incorporate CDKs, but also many other mechanisms as well. So cycle-independent kinases are very important to these checkpoints and other mechanisms of regulating the cell cycle, but they're not the only factor. They're just a very important one that's been discovered relatively recently. The final thing that I want to talk about briefly are growth factors, which are substances that stimulate cellular growth and cellular proliferation. They're usually proteins or sometimes steroid hormones.

Growth factors typically act as signaling molecules between cells. So basically certain cells will produce and excrete growth factors, which will then go and bind onto neighboring cells, telling them to grow, or to stop growing or whatever, or generally to grow because they're growth factors, or telling them to divide. In the absence of these growth factors, cells will generally enter the dormant phase or the G0 phase, where they stop growing and they don't,

duplicate DNA and they just sort of sit around. So growth factors can be very important for promoting, well, the growth and therefore ultimately the cell division. So this is why growth factors are sometimes used as hormones to get animals to grow faster and things like that. Growth factors are also very relevant to cancer research because cancer cells seem to find a way of

circumventing this process and continuing to grow even without growth factors. And it would be very interesting to find out how that happens exactly because then we could be one step closer to finding a way to stop the cancer cells from growing. Because remember, cancer cells are basically just cells that get out of control and keep dividing, even when they shouldn't essentially.

And all of these checkpoints that we talk about, you know, the cyclone-dependent kinases and the cell checkpoints and the growth factors and many other things too, all contribute to prevent this thing from happening, to prevent cell division and replication from getting out of control. But it still happens sometimes, and when that does happen, it's called cancer, and that's obviously very bad. So understanding growth factors can potentially be very useful for finding a cure for cancer or what will probably more likely finding more cures for different types of cancer, because

cancer is actually a very large category of related but distinct diseases. So, on that note, that's all I have to say in this podcast. You'll notice that I didn't talk about meiosis, which is a sort of a different version of mitosis, which occurs in sex cells. It's very similar in many of the core, in many of the key concepts, but some of the details are different because in meiosis, you only want one copy of the genetic material as opposed to two copies, and so there's various mechanisms that occur to ensure that that happens.

but I'll go into more detail about that in a future episode where I'll talk about meiosis and sexual reproduction. I think that we've already put more than enough material into this episode, so we'll leave it here for today. So, hopefully you enjoyed this episode. If you did, please jump onto iTunes and give the podcast a favorite review. I've got maybe seven or so ratings so far. I'd like a lot more than that because some of the big science podcasts have dozens or even hundreds. Also, if you could tell other people about the podcast, post it on Facebook, send people emails, talk to people in person, Any way you can spread the word is very much appreciated because I like to think that I have a good resource here in this podcast,

but I still don't have too many listeners, and so the more you can attract to the podcast, the better. Also, I'd love to hear from you. Send me an email. My address is Fods12 at gmail.com. That's F-O-D-S-1-2, as in the numerals, at gmail.com. You can send me suggestions for future topics or things you would like to see changed about the podcast. Any feedback you might have is appreciated, or even just tell me your story about how you found the podcast or when you listen to it and stuff like that. I like to hear about that as well. Find out who's listening and what you like

and what you don't like about the podcast. So, thanks again, and I'll talk to you next time.