Cell division, part 1

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					Ridge             Cell Dynamics Lecture Notes        November 5, 2009   , 12:23 PM           PAGE 1

                                     Cell division, part 1.
                         Reading: Chapter 17 pp983-1009, and Chapter 18

The cell division cycle
1.   There are some universal requirements of the cell cycle. To produce a pair of identical
     daughter cells, the DNA must be perfectly replicated, and the replicated chromosomes
     segregated into two cells.     The processes needed for these requirements are the
     minimum set needed for the cell cycle. Most cells also double their mass and duplicate
     their organelles. Thus a complex set of cytoplasmic and nuclear processes have to be
     coordinated during the cell cycle, and the central problem in cell cycle research is how
     this coordination is achieved.

2.      Recent work has shown that there is a cell cycle control system that coordinates the cycle
        as a whole, and the proteins involved in this are highly conserved. You can read about
        this in the rest of Chapter 17 of the text book, but knowledge of it is not a requirement
        for Cell Biology II.

3.      Cell cycle duration varies greatly, from as little as 8 minutes in some embryos, to as long
        as one year in liver. Most fairly rapidly dividing mammalian cells have a cycle time of
        about 24 hours.

4.      When viewed under the microscope, cells appear to be either in mitosis, or in a resting
        state between mitotic events, called interphase. Mitosis usually takes only about an
        hour, so interphase is much longer than mitosis. However, there are three distinct
        phases within interphase, and with mitosis (division), there are four successive phases in
        the ‘standard’ eucaryotic cell cycle. During interphase, one of the most important events
        is DNA replication (called S phase, S for synthesis).

5.      After division, the cell enters a rest state. This is called G 1 (G for gap) which is the gap
        between mitosis and the next round of DNA synthesis (S phase). After DNA synthesis,
        there is another gap (G2) before the cell commits to mitosis. G1 and G2 are very
        important for the cell to ready itself for division. They both provide time for additional
        growth of the cell. During G1 the cell monitors the environment and its own size, and
        when conditions are right the cell then proceeds to S phase. After DNA synthesis the G 2
        gap provides a safety time, allowing enough time for the cell to ensure DNA replication is
        `complete before commencing mitosis. The M, G1, S and G2 phases are traditional
        views of the cell cycle and work in most cases. There are exceptions however.

6.      The lengths in time of the individual phases can vary to some extent, but it is the
        duration of G1 that has the greatest variation. Some cells can enter a special resting
        state in G1, often called G0 (zero), where they can remain almost indefinitely.

7.      Some eucaryotic divisions are very short - those of early embryonic cell cycles that occur
        in certain animal embryos shortly after fertilisation. Such divisions serve to subdivide a
        giant egg into smaller cells as quickly as possible. There is no growth, G 1 and G2 are
        very short, and half the division time is spent either in M or in S.
8.      For most of the constituents of the cell, M phase is a brief interruption in what is
        generally a continuous process of transcription, translation and modification. However,
        there are some other discrete events besides nuclear division. The centrosome has to be
        duplicated so it can form the two poles of the mitotic spindle (to be discussed later). And
        there are a few key proteins that are switched on at high rate at specific stages of the
Ridge              Cell Dynamics Lecture Notes         November 5, 2009, 12:23 PM           PAGE 2

        cell cycle - for example histones are made at a high rate only in S phase (histones are
        required for the formation of new chromatin) and the same is true for some of the
        enzymes needed for DNA replication. Such events are the results of a much less easily
        observed series of sudden transitions - a control system that triggers the essential
        process of the cell cycle.

9.      The cell cycle is controlled system that triggers the start and finish of the phases. This
        controller is itself regulated at certain critical points by feedback from the processes it
        has started. There are distinct molecules that trigger the different phases.

10.     Thus the cell cycle control system is a cyclically operating biochemical device of a set of
        proteins that induce and coordinate cell division events. This system is regulated by
        feedback that can stop the cycle at specific checkpoints. This ensures that downstream
        processes are not triggered until the current phase is complete.            The feedback
        mechanisms also allow the cell cycle system to be regulated by environmental signals,
        which generally act on the control system at either a point in G 1 just before S phase
        (called the G1 checkpoint, also called Start) and the other is in G2 (the G2 checkpoint)
        just before M phase. Thus in a continuously cycling cell, the G 1 checkpoint is where the
        cell cycle control system triggers the process that starts S phase, and the G2 checkpoint
        is the point where it triggers a process that will initiate M phase.

The cell cycle control system is based on protein-kinase.
11. The cell cycle control system is based on two key families of proteins. The first is the
     family of cyclin-dependent protein-kinases (Cdk) which induce downstream processes by
     phosphorylating serines and threonines of certain proteins. The second family is of
     specialised activating proteins called cyclins, that bind to Cdk molecules and control their
     ability to phosphorylate target proteins. Thus, the cyclic assembly, activation and
     disassembly of cyclin-Cdk complexes are the pivotal events that drive the cell cycle.

12.     There are two main classes of cyclins: mitotic cyclins, which bind to Cdk molecules
        during G2 and are required for entry into M phase, and G1 cyclins, which bind to Cdk
        molecules during G1 and are required for entry into S phase. In yeast cells there is one
        Cdk that works at both checkpoints, but in mammalian cells there are at least two
        different Cdk proteins, one for each checkpoint.

13.     An outline of the events that drives a cell into mitosis:
•       mitotic cyclin accumulates during G2 and binds to Cdk to form M phase promoting factor
•       through phosphorylation by enzymes MPF is converted to an active form
•       active MPF promotes the activity of these enzymes (positive feedback)
•       MPF increases almost exponentially, rapidly reaching a critical concentration that
        activates and propels the cell into mitosis
•       MPF is equally suddenly inactivated by degradation of mitotic cyclin at the
        metaphase/anaphase boundary, enabling the cell to exit from mitosis

14.     The step at the G1 checkpoint is not so well understood, but the principles are believed
        to be similar.