Cell division

The cell division cycle

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.

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.

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.

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).

After division, the cell enters a rest state. This is called G1 (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 G2 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.

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.

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, G1 and G2 are very short, and half the division time is spent either in M or in S.

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 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.

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.

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 G1 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 G1 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 mechanics events of cell division (M phase)

mitosis cycle
prophase
prometaphase
metaphase
anaphase
telophase
cytokinesis
cell division - animal
cell division - plant

This phase includes the various stages of nuclear division (mitosis) and cytoplasmic division (cytokinesis).

Three features are unique to M phase: chromosome condensation, the mitotic spindle, the contractile ring.

Chromosome condensation is required for segregation of the chromosomes into daughter cells and is accompanied by extensive phosphorylation of histone by MPF.

Chromosomes are separated by a bipolar mitotic spindle, which is composed of MTs and MAPs, and aligns the chromosomes in a plane that bisects the cell. The spindle moves each set of daughter chromosomes to the opposite spindle poles.

A second cytoskeletal structure is the contractile ring, which is composed of actin and myosin-II, and forms just beneath the plasma membrane in a plane perpendicular to the axis of the MT spindle. The ring contracts after separation of the chromosomes, dividing the cell into two, separating not only the two sets of chromosomes but also half the parent cell contents.

Cell division also depends on the duplication of the centrosome, which is an MT organising centre (MTOC). The centrosome is a fuzzy, poorly defined area of the cell (centrosome matrix) that is associated with a pair of centrioles. Before division, the centrosome is duplicated, and each then forms the two poles of the mitotic spindle. In animal cells the centrosome closely associates with a pair of centrioles, which are thought to be involved in the duplication of the centrosome. Centrioles are not necessary for division, and are lacking in plant cells. The centrosome matrix is the important and fundamental part of the centrosome.

During interphase the centrosome is duplicated but the two centrosomes remain together on one side of the cell until mitosis. The complex then splits into two and each pair becomes a part of a MTOC that nucleates a radial array of MTs called an aster. The two asters move to opposite sides of the nucleus to form the poles of the spindle. Each daughter cell thus receives a single centrosome.

Centrosomes and centrioles remain an enigma, and still nothing is known about their substance, replication or evolutionary origin.

M phase is traditionally divided into six stages. They form a dynamic sequence. Duration of each stage varies with cell type, and they are much shorter in embryonic cell cycles. Cytokinesis begins before mitosis ends. The stages are: prophase, prometaphase, metaphase, anaphase, telophase, and cytokinesis. The first five stages constitute mitosis.

The beginning of prophase (and thus M phase as a whole) is defined as the point in which condensed chromosomes first become visible. But this is somewhat arbitrary, since chromosome condensation increases gradually and continuously during late G2. The beginning of prometaphase is defined as the moment the nuclear membrane breaks down.

A summary of the stages

by early prophase the centrosome contains two centriole pairs; chromosomes are visible

at late prophase the centrosome divides and the two asters move apart

at prometaphase the nuclear envelope breaks down (do you remember nuclear lamins?), and the spindle MTs interact with the chromosomes

at metaphase the bipolar structure of the spindle is clear and all chromosomes align across the middle of the spindle

at early anaphase, the paired daughter chromosomes (chromatids) separate synchronously and move towards the poles of the spindle

by late anaphase the spindle poles have moved apart, increasing the separation of the two groups of chromosomes

at telophase the daughter nuclei re-form

by late telophase cytokinesis is almost complete, but a midbody (remains of the spindle) persists between the two daughter cells

These stages occur in strict sequential order. Cytokinesis begins at anaphase and continues through to the end of M phase of the cell cycle.

Metaphase takes the longest time, which is not surprising considering this is the stage at which all the chromosomes are gathered at the centre. Anaphase is the quickest.

During M phase cytoplasmic organelles are fragmented or are present in large numbers to ensure they are inherited in both daughter cells. Organelles such as chloroplasts and mitochondria cannot assemble spontaneously (we have already discussed this) and it also may not be possible for ER and the GA to arise de novo. By fragmentation or by the presence of large numbers, the organelles are safely inherited in both daughter cells. ER apparently associates with MTs of the mitotic spindle, which may help with an even distribution.

As in cytokinesis, mitochondria and chloroplasts separate into daughter organelles by an actin-based contractile ring.