The Cell Cycle and Mitosis

Spec mapping: AQA 7402 Section 3.2.2 — cell cycle, mitosis and the control of mitotic division (refer to the official AQA specification document for exact wording). Required Practical 2 — mitotic index in onion root tip is anchored in this lesson.

Cell division is fundamental to multicellular life. Growth from a fertilised zygote to a multi-trillion-cell adult, the daily replacement of red blood cells (around 2 million per second), the wound-healing response to a paper cut, and the asexual reproduction of yeast and unicellular eukaryotes all depend on the controlled production of genetically identical daughter cells. When that control fails, the result is cancer — uncontrolled cell division — making the cell cycle one of the most clinically consequential topics on the AQA specification. This lesson covers the phases of the cell cycle, the mechanics of mitosis, the regulatory machinery (cyclins, CDKs, checkpoints), the cancer connection, and Required Practical 2.

Key Definition: The cell cycle is the ordered sequence of events that takes a cell from its origin in the division of a parent cell to its own division into two daughter cells. It consists of interphase (G₁, S, G₂ phases) and the mitotic phase (mitosis + cytokinesis).

---

Interphase

Interphase is the longest part of the cell cycle, typically occupying about 90% of the total cycle time. It is not a 'resting phase' — the cell is highly metabolically active.

G₁ Phase (Gap 1)

• The cell grows in size: it synthesises new proteins, produces organelles (e.g., mitochondria, ribosomes, ER), and increases its cytoplasmic volume.
• The cell carries out its normal metabolic functions.
• The cell monitors its environment and internal conditions. At the end of G₁, there is a critical checkpoint called the restriction point (R point) — if conditions are favourable (adequate nutrients, growth factors, appropriate cell size), the cell commits to DNA replication and division. If conditions are unfavourable, the cell may enter a quiescent state called G₀.

S Phase (Synthesis)

• DNA replication occurs: each chromosome is duplicated to produce two identical sister chromatids joined at the centromere by protein complexes called cohesins.
• At the end of S phase, each chromosome consists of two sister chromatids, so the cell has twice the normal amount of DNA.
• The centrioles also replicate during S phase (in animal cells).
• Histone proteins are synthesised to package the newly replicated DNA into chromatin.

G₂ Phase (Gap 2)

• The cell continues to grow and synthesise proteins needed for cell division.
• Tubulin is synthesised for the construction of the mitotic spindle.
• The cell checks that DNA replication has been completed accurately (the G₂/M checkpoint). If errors are detected, the cell cycle is paused to allow DNA repair before entering mitosis.
• The cell produces ATP stores that will provide energy for mitosis.

Exam Tip: If given a graph showing the amount of DNA per cell over time, you should be able to identify interphase (DNA doubles during S phase), mitosis (DNA halves as cells divide), and the G₁ and G₂ phases (constant DNA amounts before and after S phase).

---

Mitosis

Mitosis is the division of the nucleus into two genetically identical daughter nuclei. It is a continuous process but is described in four stages for convenience.

Prophase

• Chromatin condenses (supercoils) into visible chromosomes. Each chromosome consists of two sister chromatids joined at the centromere.
• The nuclear envelope begins to break down (disassembles into fragments that are absorbed into the ER).
• The nucleolus disappears.
• In animal cells, the two pairs of centrioles move to opposite poles of the cell.
• The mitotic spindle begins to form — microtubules extend from each centrosome (the organising centre around the centrioles). In plant cells, spindle microtubules form from diffuse microtubule-organising centres without centrioles.

Metaphase

• Chromosomes align at the metaphase plate (equator) of the cell.
• Each chromosome is attached to spindle fibres via its kinetochore — a protein complex assembled at the centromere of each sister chromatid.
• The spindle assembly checkpoint (SAC) ensures that every kinetochore is properly attached to a spindle fibre before anaphase begins. This prevents unequal chromosome distribution.

Anaphase

• The enzyme separase cleaves the cohesin proteins holding the sister chromatids together at the centromere.
• The sister chromatids are pulled apart to opposite poles of the cell by the shortening of kinetochore microtubules (depolymerisation of tubulin at the kinetochore end).
• The cell elongates as polar microtubules (which overlap at the cell centre) slide past each other.
• Each separated chromatid is now considered an individual chromosome.
• Anaphase is the shortest phase of mitosis.

Telophase

• The chromosomes arrive at opposite poles and begin to decondense (uncoil) back into chromatin.
• The nuclear envelope reforms around each set of chromosomes from ER fragments and phospholipid vesicles.
• The nucleolus reappears in each new nucleus.
• The spindle fibres disassemble.

---

Cytokinesis

Cytokinesis is the division of the cytoplasm, which follows mitosis to produce two separate daughter cells.

In Animal Cells

• A cleavage furrow forms — the cell surface membrane is pulled inward by a contractile ring of actin and myosin filaments (part of the cytoskeleton).
• The furrow deepens until the cell is pinched into two daughter cells.

In Plant Cells

• A cell plate forms at the equator of the cell.
• Vesicles from the Golgi apparatus carrying cell wall materials (pectins, hemicelluloses) are directed to the cell centre by the phragmoplast (a structure of microtubules and actin filaments).
• The vesicles fuse to form the cell plate, which grows outward until it reaches the existing cell wall, dividing the cell into two.
• A new cellulose cell wall is deposited on each side of the cell plate.

Exam Tip: Cytokinesis is separate from mitosis. Mitosis is the division of the nucleus; cytokinesis is the division of the cytoplasm. In some organisms, mitosis can occur without cytokinesis, producing multinucleate cells (e.g., striated muscle fibres).

---

Control of the Cell Cycle

The cell cycle is controlled by intracellular proteins, primarily cyclins and cyclin-dependent kinases (CDKs).

Cyclins and CDKs

• Cyclins are regulatory proteins whose concentrations fluctuate during the cell cycle (they are synthesised and degraded at specific points).
• CDKs are enzymes (kinases) that are only active when bound to their specific cyclin partner.
• The cyclin–CDK complex phosphorylates target proteins, triggering progression from one phase of the cell cycle to the next.

Example: Cyclin D accumulates during G₁ and activates CDK4/6, promoting passage through the restriction point. Cyclin B accumulates during G₂ and activates CDK1 (also known as maturation promoting factor, MPF), triggering entry into mitosis.

Checkpoints

There are three major checkpoints in the cell cycle:

Checkpoint	Location	Checks
G₁/S checkpoint (Restriction point)	End of G₁	Cell size, nutrients, growth factors, DNA damage
G₂/M checkpoint	End of G₂	DNA replication complete and accurate, cell size adequate
Spindle assembly checkpoint (SAC)	During metaphase	All chromosomes attached to spindle fibres at kinetochores

Tumour Suppressor Genes and Proto-oncogenes

• Tumour suppressor genes (e.g., p53, Rb) encode proteins that inhibit cell division or promote apoptosis when DNA damage is detected. p53 is described as the 'guardian of the genome' — when activated by DNA damage, it can halt the cell cycle at G₁ to allow repair, or trigger apoptosis if the damage is irreparable.
• Proto-oncogenes encode proteins that promote cell division (e.g., growth factors, CDKs, cyclins). Mutations that make them overactive (turning them into oncogenes) can lead to uncontrolled cell division — a hallmark of cancer.
• Cancer results from an accumulation of mutations in both tumour suppressor genes (loss of function) and proto-oncogenes (gain of function), disrupting normal cell cycle control.

Exam Tip: Loss of function of tumour suppressors (e.g., p53) and gain of function of oncogenes both contribute to uncontrolled cell division. If asked to explain how cancer develops, mention both types of genetic change.

---

Significance of Mitosis

Mitosis produces two daughter cells that are genetically identical to each other and to the parent cell (barring mutations). This is important for:

• Growth — increasing the number of cells in a multicellular organism.
• Repair — replacing damaged or dead cells (e.g., skin cells, blood cells, gut epithelium).
• Asexual reproduction — producing genetically identical offspring (e.g., binary fission in unicellular eukaryotes, vegetative propagation in plants, budding in yeast).

---

Apoptosis — Programmed Cell Death

Apoptosis is the controlled removal of cells, balancing mitotic production. It is essential for development (e.g., the loss of webbing between fingers during embryogenesis), for immune surveillance (eliminating infected or autoreactive cells), and for maintaining tissue homeostasis.

Morphological features

• The cell shrinks.
• Chromatin condenses; DNA is cleaved by endonucleases into characteristic ladder fragments (180 bp multiples).
• The nucleus fragments.
• The cytoplasm forms membrane-bound vesicles called apoptotic bodies, which are engulfed by phagocytes without releasing intracellular contents — preventing inflammation.

Mechanism

Two main pathways converge on a family of cysteine proteases called caspases.

• Intrinsic (mitochondrial) pathway: DNA damage triggers p53; p53 promotes mitochondrial outer membrane permeabilisation; cytochrome c released from mitochondria activates initiator caspases.
• Extrinsic (death receptor) pathway: ligands like FasL bind cell-surface death receptors; intracellular signalling activates initiator caspases.
• Both converge on effector caspases that cleave hundreds of cellular targets, dismantling the cell in an orderly fashion.

Apoptosis contrasts with necrosis (uncontrolled cell death — releases contents, causes inflammation). Cancer cells often acquire mutations that defeat apoptosis (e.g., loss of p53, overexpression of anti-apoptotic Bcl-2 family proteins), allowing them to survive DNA damage and accumulate further mutations.

---

Cancer Therapy Targeting the Cell Cycle

Many cancer chemotherapeutics exploit the rapid mitosis of tumour cells, accepting collateral damage to other rapidly dividing tissues (gut, bone marrow, hair follicles — explaining the characteristic side-effects).

• Antimitotic drugs: vinca alkaloids (vincristine, vinblastine) bind tubulin and prevent spindle assembly; taxanes (paclitaxel) stabilise microtubules and prevent depolymerisation. Both halt mitosis at metaphase.
• DNA-damaging agents: alkylating agents (cyclophosphamide), platinum compounds (cisplatin), and topoisomerase inhibitors (etoposide) damage DNA and trigger p53-dependent apoptosis. Most effective on cells with intact p53, which paradoxically means some highly malignant p53-mutant tumours are resistant.
• Antimetabolites: 5-fluorouracil, methotrexate inhibit nucleotide synthesis, halting S-phase.
• Targeted therapies: imatinib (BCR-ABL kinase inhibitor in chronic myeloid leukaemia), CDK4/6 inhibitors (palbociclib in breast cancer) target specific cell-cycle components.

Newer immunotherapies (checkpoint inhibitors like pembrolizumab, CAR-T cells) work through the immune system rather than directly targeting the cell cycle; they will be covered in lesson 9.

---

Stem Cells and the Cell Cycle

Some cell types must remain capable of dividing throughout life. These are stem cells, which self-renew (maintaining the stem-cell pool) and differentiate into specialised cells (producing the differentiated tissue).

• Haematopoietic stem cells in bone marrow give rise to all blood cell lineages.
• Intestinal stem cells at the base of crypts give rise to the rapidly renewing gut epithelium (renewed every 4–5 days).
• Hair follicle stem cells drive hair growth cycles.
• Embryonic stem cells are pluripotent — capable of forming any cell type.
• Induced pluripotent stem cells (iPSCs) are differentiated cells reprogrammed by transcription factors to a stem-cell-like state (Shinya Yamanaka, 2012 Nobel Prize).

Most differentiated cells exit the cell cycle into G₀. They may re-enter the cycle on appropriate stimulation (e.g., liver hepatocytes after partial hepatectomy). Some are terminally differentiated and never re-enter the cycle (e.g., mature neurones, cardiac myocytes — explaining why the brain and heart have very limited regenerative capacity).

This integration of cell-cycle regulation with development and tissue maintenance is one of the major themes of contemporary biology, and is examined synoptically across the AQA spec.

---

Mermaid Diagram — Cell Cycle Phases

flowchart LR
  G1[G1 cell grows] --> R{Restriction point}
  R -- favourable --> S[S DNA replicates]
  R -- unfavourable --> G0[G0 quiescent]
  S --> G2[G2 prepares for mitosis]
  G2 --> Check{G2/M checkpoint}
  Check --> M[M mitosis + cytokinesis]
  M --> G1

---

Required Practical 2 — Mitotic Index in Onion Root Tip

This practical uses light microscopy to count cells in different stages of the cell cycle and to calculate the mitotic index — the proportion of cells in mitosis at any one time.

Aim

Determine the mitotic index of onion root tip cells and use it to infer the proportion of the cell cycle spent in mitosis.