Cell Cycle Controls

by Georgina Cornwall, PhD

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    00:00 So let's look now at some of the details of each of these phases in the cell cycle and how they're controlled.

    00:08 What really determines whether a cell moves on through each of these phases has to do with some of the cell signalling and communication that we've previously learned about.

    00:19 So to begin with, we have three checkpoints, three major checkpoints.

    00:25 There's a checkpoint between G1 and S. We need to make sure everything is ready for synthesis to occur otherwise we don't need to move into synthesis yet.

    00:36 So when the cell "decides" to divide, it's really getting signals about whether it's ready to divide.

    00:43 Some of these might be external signals. For example, I introduced previously autocrine signaling.

    00:50 During development, a cell is going to produce some substances that say "Hey, I'm ready to move into another round of cell division".

    00:58 In this case, they spend a short amount of time in G1 and move straight on into synthesis and continue division.

    01:05 So growth factors are involved. You'll recall that growth factors often work with receptor tyrosine kinases.

    01:12 This is one of those checkpoints that once the cell has put together the machinery for DNA synthesis we're not going to go back, right. So DNA synthesis enzymes are in place, we're moving forward into the synthesis phase.

    01:28 So the next checkpoint is the G2M checkpoint. So a checkpoint to see that everything is ready all the machinery is actually in place to go into mitosis or cell division.

    01:39 We need to have proteins, microtubules, so we can produce the spindle apparatus that's involved in cell division and so on and so forth.

    01:48 If we are ready for that, then we move into mitosis.

    01:54 And so we have M-Phase promoting factors that help a cell decide if it's ready to move into M phase, and these mitosis promoting factors are going to assess whether the DNA was replicated correctly.

    02:10 And if it was replicated correctly, can we move on into M phase. Cause we don't want to have improperly replicated DNA going into M phase and having cell division. So we have natural checks and controls to make sure everything is in place and we're good to go.

    02:28 The final checkpoint that we'll look at here is the spindle checkpoint.

    02:33 Now the spindle checkpoint is where we're checking that all the machinery. Once we've lined up chromosomes on the metaphase plate which we'll learn about when we explore M phase.

    02:43 Once the chromosomes are lined up on the metaphase plate and the fibres are in place to pull the chromosomes apart, we want to check that they're actually attached properly and that we're going to separate chromosomes in a matter that ends up having one of each copy in each cell.

    03:00 If things are not set up properly, then we won't proceed.

    03:04 Again, checks and balances are in place to make sure that we're ready to separate the chromosomes and actually divide the nucleus and then go through cytokinesis and divide the cell.

    03:16 So what happens here is, if it's not ready to go, then the cell does not divide, sometimes the cell will be destroyed, sometimes the DNA will be repaired before we go into cell division, but it's another irreversible checkpoint.

    03:32 Once you passed it, cell division is happening.

    03:36 So chromosomes are going to be arranged correctly or incorrectly. If they're not arranged correctly, no moving forward.

    03:43 And if the spindle fibres are not attached correctly to the connector cores in order to pull the chromosomes apart, then we're not moving forward.

    03:52 So what are these mitosis promoting factors though? Turns out that there are two proteins involved in moving forward into mitosis and initiating the transcription and translation of all of the proteins, microtubules and such that are involved in pulling chromosomes apart or breaking the bonds between chromosomes.

    04:18 We have cyclin dependent kinases or Cdk's as well as cyclins. The Cdk's are dependent on the cyclins.

    04:29 There are a number of different cyclins and Cdk's that we've identified and different ones work at different checkpoints which makes sense because if the same one works then we would promote one phase which would also promote the others.

    04:45 So we have to have different partnerships of cyclin dependent kinases and cyclins.

    04:51 So the cyclin dependent kinases are activated by cyclin. We have a standard level of the cyclin dependent kinases in the cell of course a few more are made when it's time to go into mitosis.

    05:04 As we prepare and things are getting ready to go through one of the checkpoints the cyclin content will increase, and we'll see more and more cyclins, and we'll see phosphorylation, so that the cyclins can bind onto the cyclin dependent kinases and become phosphorylated and start the process of the next phase of the cell cycle.

    05:29 So the first checkpoint that we'll look at in detail is this G1S checkpoint.

    05:34 The G1S checkpoint involved cyclin dependent kinase 2, probably because it was the second cyclin dependent kinase that we learned about.

    05:43 Cyclin dependent kinases in the cell at a fairly consistent level and then increasing levels of cyclin E are produced.

    05:55 As we see higher and higher levels of cyclin E, we see more cyclin E bound to the cyclin dependent kinase for that step in the game.

    06:06 And that we'll see activation, so that we're producing all of the factors that are necessary to move into S phase.

    06:13 Everything is checked. Everything is balanced. We're good to go.

    06:17 Increasing the enzyme production for DNA synthesis is going to happen after this checkpoint.

    06:22 So it's irreversible. We are going to be synthesizing DNA once it's passed.

    06:27 The next checkpoint is the G2M checkpoint, and at this checkpoint we have a different cyclin.

    06:35 Makes sense to have a different one, right. Otherwise the cyclin dependent kinase and the cylin from the previous phase could stimulate the cell to move forward. We don't want that.

    06:45 So different cyclin and a different cyclin dependent kinase come together in order to promote movement into mitosis.

    06:53 Activation of these proteins, these cyclin dependent kinases allow the cyclin to be phosphorylated and allow other proteins to be phosphorylated.

    07:04 As we've explored before, cell communications involved lots of passage of phosphates to different proteins in order to result in transcription and translation of the necessary machinery for that signal to have an effect in the cell.

    07:22 So, the final checkpoint, the other irreversible checkpoint is the spindle checkpoint. This is a really important checkpoint.

    07:30 We need to make sure chromosomes are aligned well before we pull them apart and start shortening the microtubules and separating things. If things aren't set up right, then we're going to have missing chromosomes in one cell or the other and that's really not a great situation. So this spindle checkpoint involves the production of anaphase-promoting complex which tells you that we're probably not in anaphase yet, right.

    07:59 So we're in metaphase, this is where we're having chromosomes aligned on the metaphase plate.

    08:05 And once we have these anaphase-promoting complexes, we will see the machinery work and actually pull the chromosomes apart.

    08:16 So it's thought that these anaphase-promoting complexes result from tension on the spindle fibres or the microtubules that are starting to pull the chromosomes apart.

    08:31 So as they start to pull, perhaps that's the trigger for these anaphase-promoting complexes Not really clear on the mechanism of how they work as we are with the Cdk and cyclin pairing but something's working there to determine whether we'll move into anaphase.

    08:51 So what happens here is these anaphase-promoting complexes will start helping to breakdown the connects and proteins between the two sister chromatids so that they can actually separate and be pulled to the opposite poles of the cell and complete cell division.

    About the Lecture

    The lecture Cell Cycle Controls by Georgina Cornwall, PhD is from the course Cell Cycle and Cell Division.

    Included Quiz Questions

    1. G1 to S to G2 to mitosis to cytokinesis
    2. G1 to G2 to S to mitosis to cytokinesis
    3. G1 to S to G2 to cytokinesis to mitosis
    4. S to G1 to G2 to mitosis to cytokinesis
    1. G2
    2. G1
    3. S
    4. M
    1. APC—Phosphorylation of DNA polymerase
    2. G2M checkpoint—Commitment to mitosis
    3. Spindle checkpoint—Deal with DNA separation
    4. G1S—Deals with DNA synthesis
    5. MPF—Assess the success of DNA synthesis
    1. There is only one set of Cdk and cyclins to control the cell cycle checkpoints to make the process a less complicated cell chore.
    2. Spindle and G1S checkpoints are irreversible clearance points in the cell cycle.
    3. Clearance of G2M phase leads to the activation of proteins necessary for the formation of mitosis machinery.
    4. Anaphase promoting complex (APC) involves removal of cohesion from the chromosomes during separation of sister chromatids.
    5. During G1S checkpoint, the binding of cyclin E to Cdk2 triggers the synthesis of various proteins involved in DNA synthesis.

    Author of lecture Cell Cycle Controls

     Georgina Cornwall, PhD

    Georgina Cornwall, PhD

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