Cell Cycle

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Cell cycle

The cell cycle is the cyclical process by which a cell that has just divided grows, replicates its DNA, and then divides again. In eukaryotes, it is generally considered to have four phases:

  1. G1 - the first gap phase, during which the cell grows to a threshold size. The cell actively takes up materials from its environment to form new organelles and cytoplasm.
  2. S - during which the cell replicates its DNA and MTOCs (microtubule organising centres: i.e. centrioles, centrosomes, etc.)
  3. G2 - the second gap phase, during which the cell condenses its genome and MTOCs begin to form a spindle which will later separate the chromosomes.
  4. M - mitosis (or meiosis), during which the genome is passive, whilst the cytoskeleton actively moves the chromosomes about.

Cell cycle cartoon.

The speed of the cell cycle (and its equivalent in bacteria) is highly variable: Escherichia coli's genome is 5 Mbp and takes 40 minutes to replicate; however, that of Plasmodium falciparum is 2.7 Gbp but takes only 8 minutes to replicate. This is because there are multiple replication forks per chromosome in eukaryotes, but only one in most prokaryotes. Prokaryotes can also reproduce more quickly than their genomes, because replication can occur whilst the cell is dividing.

Transfer between phases of the cell cycle is regulated by soluble inducers: an M-phase cytoplasm will induce condensation of interphase nuclei if two cells are fused. These soluble inducers are proteinaceous, and usually formed from a cyclin and a cyclin-dependent kinase. They allow the cell to pass through 'check-points' in the cell cycle.

Progression of the cell cycle from G1 to S is under the control of a number of DNA-auditing proteins such as p53, which affect the interaction between cyclin proteins and cyclin-dependent-kinases (CDKs). Cyclin E interaction with CDK-2 is required for progression from G1 to S: the binding of these units produces S-kinase activity, which activates and inactivates appropriate proteins (such as transcription factors). If the DNA is damaged, kinase activity is reduced by p53, which accumulates in response to DNA damage. p53 is consequently important in understanding cancers. If the cell has failed to grow, it will enters G0 phase, a quiescent 'waiting room' in the cycle.

In S phase, the cell duplicates its DNA. In G2, the cell finds out if all of its DNA has been correctly replicated. Progression from the G2 checkpoint to mitosis appears to be under the control of p34 and cyclin B, which again form a kinase pair (M-kinase or maturation promoting factor, MPF) under the influence of other 'cell-checking' proteins. In M (mitosis or meiosis) phase, there is another checkpoint at the end of metaphase, where the cell checks that all its chromosomes are correctly aligned on the metaphase plate. Progression from M back to G1 occurs only if these conditions are satisfied.

Mitosis

Mitosis is the process by which a eukaryotic cell divides. It is divided into several phases. At the end of mitosis, the two chromatids of each chromosome - which have been produced during S-phase - are separated: each chromatid becomes the chromosome of the new cell.

Phases of mitosis

Prophase

Most of the action is in the cytoskeleton: the MTOCs (centrosomes/centrioles) move apart and microtubules depolymerise: their t½ drops from about 5 min to 15 s. The asters then form by resynthesis from tubulin, with their minus end in the MTOC as usual. Microtubule organising centres are the centrosomes with their embedded centrioles in animals. Plants have less well defined MTOCs. The basal bodies of undulipodia (eukaryotic flagella and cilia) are interchangeable with MTOCs, and often serve double-duty in protoctists.

The nucleolus is lost, so rRNA is no longer synthesised.

Histone H1 become 6-fold phosphorylated, and begins condensation of chromosomes, whose telomeres stick to the inner nuclear envelope.

Prometaphase

All nuclear lamins become phosphorylated and the nuclear envelope breaks down into vesicles. Lamin B remains in the vesicle, and is probably required for regeneration of the nuclear envelope during telophase.

The cytoskeleton invades the genome and kinetochores form on centromere. These are three layered structures bound to AT-rich repeats on centromeres:

Kinetochores are three-layered structures that form on the centromeres.

Antibodies from sufferers of autoimmune (CREST) scleroderma bind kinetochore proteins; proto-kinetochores seem to exist even during interphase.

Metaphase

The chromosomes are held in tension at the metaphase plate by a tug of war between tread-milling (continually depolymerising and repolymerising) kinetochore microtubules.

Microtubules hold the chromosomes at the metaphase plate by treadmilling.

Lamins and histones begin to lose phosphorylation.

Anaphase

Microtubules shorten by depolymerisation at their + ends, and the kinetochore 'rides up' this wave of depolymerisation. The chromosomes are dragged apart at c. 1 µm min−1.

Microtubules pull the chromosomes apart by depolymerisation at their plus ends.

Telophase

The nuclear envelope reforms around DNA from lamin B containing vesicles: Any DNA will do, even prokaryotic. Chromosomes decondense as histone H1 loses phosphorylation.

Cytokinesis

During cytokinesis, the actin microfilaments get to work. These form a midbody bridge, and constrict the cytoplasm into a cleavage furrow that pinches the daughter cells apart.

In plants, a phragmoplast of microtubules traps Golgi vesicles to form the cell plate. This matures into the cell wall, with the ER trapped across the cell plate becoming plasmodesmata.

Single-copy organelles are also precisely redistributed. Endosymbionts reproduce by binary fission, and apportion between the cells as the cytoplasm is divided.

Test yourself

  1. What is the role of the nuclear lamins in the cell cycle, and how are they regulated?
  2. Describe the important steps of the cell cycle.

Answers

Bibliography

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