Cell Cycle and Cell Division (IB Biology): Interphase, Mitosis, Meiosis and Cancer

Intro What is the cell cycle?

Syllabus link: D2.1.1 Generation of new cells by cell division; D2.1.4 Roles of mitosis and meiosis; NCERT 10.1

AHL = additional higher level (IB HL only)   NCERT = extra detail for NEET / CBSE students (beyond the IB guide)

The cell cycle is the sequence of events by which a cell grows, replicates its DNA and then divides to form two daughter cells. Every cell in your body, apart from the very first one (the zygote), was made this way, so understanding the cell cycle explains how organisms grow, heal and reproduce.

Cell division is the biological process in which a parent cell (often called the mother cell) divides into two daughter cells. In 1855 Rudolf Virchow proposed that all cells arise from pre-existing cells (omnis cellula e cellula), and cell division is the process that makes this true.

The formation of daughter cells is much simpler in prokaryotic cells than in eukaryotic cells. A prokaryotic cell contains a single circular chromosome. The chromosome first replicates and the two copies of DNA separate as the cell elongates. The parent cell then splits into two daughter cells. This is called binary fission.

Eukaryotic cells are more complex: they have many linear chromosomes inside a nucleus, and many membrane-bound organelles. All these components must be duplicated and shared out during cell division. To do this, eukaryotic cells pass through a series of stages called the cell cycle.

Why do cells divide?

• Growth. A human starts as one cell, the zygote, and an adult body has roughly 30 to 40 trillion cells.
• Replacement. Cells of the skin, the lining of the gut and the blood are lost all the time and must be replaced.
• Repair. Cells divide to close a wound or regrow damaged tissue.
• Asexual reproduction. Single-celled organisms such as Amoeba and yeast reproduce by dividing.
• Sexual reproduction. Meiosis makes the haploid gametes (or, in plants, spores) needed for a sexual life cycle.

Two kinds of nuclear division

In eukaryotes the nucleus must divide before the cell divides, otherwise one daughter cell would have no nucleus (an anucleate cell). There are two kinds of nuclear division:

• Mitosis keeps the chromosome number the same and gives two genetically identical nuclei. It is used for growth, repair, replacement and asexual reproduction.
• Meiosis halves the chromosome number (diploid to haploid) and gives four genetically different nuclei. It is used to make gametes or spores.

The division of the cytoplasm that follows nuclear division is called cytokinesis. Sections 2 to 4 deal with mitosis, cytokinesis and meiosis in turn; sections 5 and 7 show how the cell cycle is controlled and how cancer results when that control breaks down.

1 Phases of the cell cycle: interphase, G₀ and duration

Syllabus link: D2.1.5 DNA replication as a prerequisite for mitosis and meiosis; AHL D2.1.13 Phases of the cell cycle; AHL D2.1.14 Cell growth during interphase; NCERT 10.1

Every eukaryotic cell that divides goes through a well-defined sequence of events called the cell cycle. In one cell cycle a cell first grows, then replicates its DNA, and finally divides to form two daughter cells.

Features of the cell cycle

• Coordinated: the events of the cell cycle happen in a fixed order, and each one is completed before the next begins.
• Under genetic control: the events are controlled by genes, through proteins such as cyclins and kinases (section 5).
• DNA replication happens once in each cell cycle, during S phase.
• Growth is continuous: unlike DNA replication, cell growth carries on through interphase.

The two main phases: interphase and M phase

The cell cycle has two main phases: interphase, when the cell prepares for division, and the M phase (mitotic phase), when the cell actually divides.

• M phase (mitosis phase) is when the cell divides. Division of the nucleus (karyokinesis) is followed by division of the cytoplasm (cytokinesis).
• M phase is short: less than 5% of the cell cycle.
• Interphase is the period between two successive M phases. The cell grows and prepares itself for division. It takes more than 95% of the cell cycle.
• Interphase is divided into three phases: G₁, S and G₂.
• Interphase is sometimes called the ‘resting phase’, but the cell is not resting: it is growing, making proteins and replicating its DNA. It is better to call it the preparation phase.

What happens during G₁ phase?

• G₁ (first gap) is the interval between the end of M phase and the start of S phase. It is also called the post-mitotic phase.
• The cell is metabolically very active and grows a lot. Growth needs proteins and enzymes, so transcription and translation are busy.
• Organelles such as mitochondria and ribosomes increase in number.
• Near the end of G₁ the cell ‘decides’ what to do next: (a) continue the cycle and enter S phase, or (b) leave the cycle and enter the G₀ (quiescent) phase.
• Cells that will divide pass the G₁ checkpoint and move into S phase. Cells that leave the cycle stay in G₀; some return to G₁ later if they receive a signal to divide.

What happens during S phase?

• S stands for synthesis (DNA synthesis). It is the only phase in which DNA replication takes place.
• DNA replication is semi-conservative: the two strands of each DNA double helix separate and each acts as a template for a new strand, giving two identical double-stranded molecules.
• The amount of DNA doubles. If a diploid cell has 2C DNA in G₁, it has 4C at the end of S phase.
• The number of chromosomes does not change. Each chromosome now consists of two identical sister chromatids joined at the centromere.
• Histone proteins are made in large amounts, because the newly made DNA must be wrapped around histones.
• In animal cells the centriole pair duplicates in the cytoplasm. (Most plant cells have no centrioles; they still build a spindle.)
• So, DNA replication takes place in the nucleus, while histone synthesis and centriole duplication take place in the cytoplasm.
• Chromatin exists in two forms: loosely packed euchromatin and densely packed heterochromatin. Euchromatin is replicated early in S phase and heterochromatin later.

What happens during G₂ phase?

• G₂ (second gap) is the interval between S phase and M phase. It is also called the post-synthetic or pre-mitotic phase.
• The cell continues to grow and makes the proteins needed for mitosis.
• Tubulin is made in large amounts; it is the protein from which spindle microtubules are built.
• Mitochondria (and chloroplasts in plant cells) keep increasing in number by growth and division; this happens through interphase, not only in G₂.
• The cell checks that DNA replication is complete and that any damage has been repaired before it enters mitosis (the G₂ checkpoint).

G₀: the quiescent phase

Some cells stop dividing. They leave the cycle at G₁ and enter an inactive stage called G₀, the quiescent stage. Cells in G₀ are alive and metabolically active: they carry out their normal jobs, but they no longer proliferate unless they are signalled to do so.

• Can re-enter the cycle: liver cells (hepatocytes) return to G₁ when part of the liver is damaged or removed; lymphocytes divide when they meet an antigen.
• Rarely or never re-enter: most nerve cells (neurons) and heart muscle cells are fully differentiated and stay in G₀ for life. These are sometimes called permanent cells.

How long does a cell cycle take?

The length of the cell cycle varies from organism to organism and from one cell type to another. Yeast can complete a cycle in about 90 minutes. A typical human cell in culture divides about once every 24 hours, and cell division proper (M phase) lasts only about one hour of this.

For most dividing cells the phases rank G₁ > S > G₂ > M in duration, so G₁ is usually the longest phase and M phase the shortest. G₁ is also the most variable: in very fast embryonic divisions it is almost absent.

Chromatin, chromosomes and chromatids

During interphase, chromosomes cannot be seen as separate structures under the light microscope; the nucleus contains chromatin. Chromatin is the uncondensed, thread-like form of DNA with its proteins. A chromosome is the condensed, division-ready form of the same DNA, which becomes visible only during M phase.

• Single chromatid = one double-stranded DNA molecule.
• Chromosomes are counted by centromeres. A duplicated chromosome (two sister chromatids, one centromere) still counts as one chromosome.
• n = one complete set of chromosomes (one copy of each type). 2n = two sets. In humans 2n = 46 and n = 23.
• C = the amount of DNA in one haploid set. It tracks DNA, not chromosomes. A diploid cell is 2C in G₁ and 4C in G₂.

DNA amount and chromosome number through the cycle

Take an example of a cell with 2n = 6: 6 chromosomes, made of 3 homologous pairs (n = 3, so one set has 3 chromosomes). In humans 2n = 46 and n = 23: there are two sets, each containing 23 different types of chromosome.

Swipe sideways to see the whole table →

Notice two things in the table. First, S phase doubles the DNA (2C to 4C) but not the chromosome number. Second, in anaphase each chromatid becomes an independent chromosome, so for a short time the cell contains twice the usual number of chromosomes (12 here, 92 in a human cell) until cytokinesis shares them out.

Worked examples

Q1. The number of chromosomes in a gamete is 10. Find the amount of DNA in G₂ and the number of chromosomes in a body cell.

Answer. A gamete is haploid, so n = 10 and body cells have 2n = 20. If the body cell has 2C DNA in G₁, the DNA amount in G₂ is 4C, but the number of chromosomes stays 20.

Q2. You have studied mitosis in onion root tip cells, where each cell contains 16 chromosomes. How many chromosomes are present in a cell during G₁, after S phase and after M phase? If the DNA content of a cell after M phase is 2C, what is the DNA content during G₁, after S phase and during G₂?

• Chromosome number (counted by centromeres): G₁ = 16; after S phase = 16 (each now has two sister chromatids); after M phase = 16 in each daughter cell.
• DNA content changes because DNA is replicated in S phase: G₁ = 2C (the same as after M phase); after S phase = 4C; G₂ = 4C (still duplicated, no division yet).

2 Mitosis: prophase, metaphase, anaphase and telophase

Syllabus link: D2.1.6 Condensation and movement of chromosomes; D2.1.7 Phases of mitosis; D2.1.8 Identification of phases of mitosis; AHL D2.1.12 Cell proliferation; NCERT 10.2, 10.3

Mitosis is the division of the nucleus that produces two nuclei with the same number and type of chromosomes as the parent nucleus. Because the chromosome number stays the same, mitosis is called an equational division.

Features of M phase

• Major reorganisation of the nucleus and the cytoplasm: the nuclear envelope breaks down and a spindle is built.
• Equational division: daughter nuclei are genetically identical to the parent nucleus.
• Can occur in both haploid and diploid cells.
• M phase has two parts: karyokinesis (nuclear division) and cytokinesis (division of the cytoplasm).
• Karyokinesis is divided into four stages: prophase, metaphase, anaphase and telophase. Prophase usually takes the longest and anaphase the shortest time.

Condensing and moving chromosomes

Two problems have to be solved in every mitosis and meiosis (D2.1.6). First, very long DNA molecules must be packed into short, compact chromosomes that can be moved without tangling. DNA is wound around histone proteins to form nucleosomes, and the chain of nucleosomes is then coiled and looped again and again (supercoiling). A human chromosome can become thousands of times shorter than its DNA.

Second, the chromosomes must be moved. This is done by the spindle, made of microtubules. Microtubules attach to the kinetochore, a protein structure on each centromere. Motor proteins at the kinetochore and along the spindle use ATP to move chromosomes, while microtubules shorten by losing tubulin subunits, pulling chromatids towards the poles.

Prophase

Prophase is the first stage of karyokinesis. It follows the S and G₂ phases of interphase, so every chromosome already consists of two sister chromatids. By the end of prophase:

• Chromatin condenses to form compact chromosomes, each with two visible sister chromatids.
• The two centrosomes, which duplicated during interphase, move towards opposite poles of the cell, and the spindle starts to form between them.
• The nucleolus disappears, and the Golgi apparatus and endoplasmic reticulum break up into small vesicles, so they are no longer seen under the microscope.
• The nuclear envelope breaks down into fragments.

A centrosome contains two centrioles at right angles, surrounded by protein material. Microtubules radiating from each centrosome form a star shape called an aster. Animal cells have two asters, so their spindle is called amphiastral. Most plant cells have no centrioles and no asters; their spindle is anastral. The two asters together with the spindle fibres form the mitotic (spindle) apparatus. In prophase the spindle fibres have not yet attached to the chromosomes.

Metaphase

• The nuclear envelope has completely disappeared, and the chromosomes are spread through the cytoplasm.
• Chromosomes are fully condensed. Metaphase is the best stage to study chromosome number and shape (morphology), which is why karyotypes are made from metaphase cells.
• Spindle fibres attach to the kinetochores, the disc-shaped protein structures on the surface of each centromere. The kinetochore of one sister chromatid is attached to fibres from one pole, and the kinetochore of its sister to fibres from the opposite pole.
• Pulling from both sides brings all the chromosomes to the equator of the spindle. The plane where they line up is called the metaphase plate.

Anaphase

• The centromere of each chromosome splits and the sister chromatids separate from each other, all at the same moment.
• Each separated chromatid is now called a daughter chromosome of the future nuclei.
• Kinetochore microtubules shorten and pull the daughter chromosomes to opposite poles. The centromere leads, and the arms trail behind.
• Other spindle microtubules lengthen and push the poles apart, so the cell elongates.

Because the arms trail behind the centromere, chromosomes take different shapes in anaphase depending on where the centromere is:

• Metacentric (centromere in the middle): V-shaped.
• Sub-metacentric (centromere slightly off-centre): L-shaped.
• Acrocentric (centromere very close to one end): J-shaped.
• Telocentric (centromere at the end): I-shaped, a straight rod.

How sister chromatids are held together and released

Sister chromatids are held together along their length, and most strongly at the centromere, by rings of a protein called cohesin. When every kinetochore is attached to the spindle, a protein complex called the anaphase-promoting complex (APC/C) becomes active. APC/C is not itself the enzyme that dissolves cohesin. It tags an inhibitor protein, securin, for destruction. With securin gone, the enzyme separase becomes active and cuts the cohesin, so the sister chromatids can be pulled apart. APC/C also tags mitotic cyclin for destruction, which lets the cell finish mitosis.

If APC/C does not work, securin is not destroyed, cohesin is not cut and the cell stays stuck in metaphase. (This is different from polyteny: polytene chromosomes, as in the salivary glands of Drosophila larvae, form when DNA is replicated many times without any mitosis, so hundreds of chromatids stay side by side.)

Colchicine and polyploidy

The alkaloid colchicine, from the autumn crocus, binds to tubulin and stops microtubules forming, so no spindle can be built. The chromosomes condense and the centromeres still split, but the chromatids are not pulled to the poles. When the nuclear envelope reforms, the cell has a single nucleus with double the chromosome number. Repeating this gives polyploid cells, and plant breeders use colchicine to make polyploid crop varieties.

Telophase

• Chromosomes reach the poles and decondense, losing their identity as separate chromosomes and becoming chromatin again.
• A nuclear envelope re-forms around each group of chromosomes.
• The nucleolus, endoplasmic reticulum and Golgi apparatus re-form.
• The spindle disappears.
• Two genetically identical nuclei are formed. Cytokinesis usually begins during telophase.

Identifying the phases of mitosis

IB students must be able to identify the phases in diagrams, micrographs and slides (D2.1.8). Root tip squashes of onion or garlic are the usual practical. Look for these clues:

Where does mitosis occur?

• Gut lining: cells lining the alimentary canal are replaced every few days.
• Skin: cells in the deepest layer of the epidermis divide continuously to replace cells lost from the surface.
• Red bone marrow: stem cells divide to produce blood cells. Mature red blood cells have no nucleus and cannot divide themselves.
• Plant meristems: apical meristems at root and shoot tips cause growth in length (primary growth); lateral meristems (vascular cambium and cork cambium) increase girth (secondary growth).

Mitosis in haploid and diploid cells

In animals such as humans (2n = 46), body cells are called somatic cells. They are diploid, and new somatic cells are formed by mitosis. Diploid germ cells in the ovaries and testes form haploid gametes (n = 23) by meiosis. In most animals the gametes never divide by mitosis, so mitosis happens only in diploid cells.

Exception: the honey bee. A queen honey bee (2n = 32) forms egg cells (n = 16) by meiosis. An unfertilised egg develops into a drone (male), which is therefore haploid (n = 16). The drone makes its male gametes by mitosis, so in honey bees mitosis happens in haploid cells too. Fertilised eggs (2n = 32) develop into females: workers or queens.

In plants, mitosis occurs in both haploid and diploid cells. The diploid sporophyte grows by mitosis; meiosis makes haploid spores; the spores grow into a haploid gametophyte by mitosis; and the gametophyte makes gametes by mitosis. Fertilisation restores the diploid number in the zygote.

Significance of mitosis

• Produces daughter cells with the same chromosome number and identical genetic information as the parent (genetic stability).
• Growth of multicellular organisms, from the zygote onwards.
• Restores the nucleo-cytoplasmic ratio: as a cell grows, its cytoplasm increases but its nucleus does not, and division restores the balance.
• Cell repair and replacement, for example in the epidermis, the lining of the gut and the production of blood cells.
• Continuous growth of plants from meristems (apical and lateral).
• Asexual reproduction and vegetative propagation, which produce genetically identical offspring.
• It occurs in both haploid and diploid cells.

3 Cytokinesis: cleavage furrow and cell plate

Syllabus link: D2.1.2 Cytokinesis as splitting of cytoplasm; D2.1.3 Equal and unequal cytokinesis; NCERT 10.2.5

Cell division is complete only after cytokinesis, the division of the cytoplasm and its organelles between the two daughter cells. It usually starts in late anaphase or telophase.

In some organisms karyokinesis is not followed by cytokinesis. The nuclei keep dividing inside one mass of cytoplasm, giving a multinucleate cell called a syncytium. A well-known example is the liquid endosperm of coconut (coconut water), which contains many free nuclei; endosperm nuclei are triploid (3n).

Cytokinesis in animal cells: the cleavage furrow

Animal cells have no cell wall; they are bounded only by the plasma membrane. Just under the membrane, around the equator of the cell, a contractile ring of actin filaments and myosin forms. Myosin pulls the actin filaments past each other, so the ring tightens like a drawstring. The membrane is pulled inwards, forming a cleavage furrow that deepens until the cell is pinched into two daughter cells.

Cytokinesis in plant cells: the cell plate

Plant cells have a rigid cell wall that cannot be pinched inwards. Instead, vesicles from the Golgi apparatus, carrying wall materials such as pectins, are guided by microtubules to the equator. They fuse to form a flat sac, the cell plate. The cell plate starts in the centre and grows outwards (centrifugally) until it joins the existing side walls. The vesicle membranes become the new plasma membranes of the two cells, and their contents form the middle lamella, made mainly of calcium pectate. Each daughter cell then lays down cellulose on its side to complete its new primary wall. The two daughter cells stay joined by the middle lamella; they do not separate.

Equal and unequal cytokinesis

Cytokinesis is usually equal, giving two daughter cells of similar size. It does not have to be equal, but each daughter cell must receive at least one mitochondrion (and, in plants, a plastid), because these organelles can only be made by division of an existing one.

• Oogenesis in humans: both divisions of meiosis are unequal. Almost all the cytoplasm goes to the secondary oocyte and then to the ovum, while the tiny polar bodies get very little and later die. The ovum keeps a large store of nutrients and organelles for the early embryo.
• Budding in yeast: the nucleus divides by mitosis, but one nucleus moves into a small outgrowth (the bud), which pinches off as a smaller daughter cell.

4 Meiosis: the reduction division

Syllabus link: D2.1.9 Meiosis as a reduction division; D2.1.10 Down syndrome and non-disjunction; D2.1.11 Meiosis as a source of variation; NCERT 10.4, 10.5

Meiosis is the nuclear division that halves the chromosome number, producing four haploid (n) nuclei from one diploid (2n) nucleus. Because the chromosome number is reduced, meiosis is called a reduction division.

Meiosis is needed in every sexual life cycle. Fertilisation fuses two gametes and doubles the chromosome number; without a halving step somewhere in the life cycle, the chromosome number would double in every generation. In animals meiosis makes gametes; in plants it makes spores.

Key features of meiosis

• Two divisions, meiosis I and meiosis II, but only one round of DNA replication (in the S phase before meiosis I).
• Homologous chromosomes pair up in prophase I to form bivalents, and crossing over occurs between non-sister chromatids.
• Two rounds of segregation: homologous chromosomes separate in meiosis I; sister chromatids separate in meiosis II.
• The result is four haploid cells that are genetically different from each other and from the parent cell.

Homologous chromosomes are a matching pair, one from each parent (shown magenta for the maternal and purple for the paternal homologue in the diagrams below, in a cell with 2n = 4: one long pair and one short pair). They have the same genes in the same order, although the alleles of those genes may differ. A pair of homologous chromosomes held together in prophase I is a bivalent; because it has four chromatids it is also called a tetrad.

Meiosis I

Follow the two long and two short chromosomes through every diagram: each bivalent has one crossover, so after meiosis I one chromatid of each chromosome carries a tip of the other colour.

• Prophase I: chromosomes condense; homologues pair (synapsis) to form bivalents; crossing over occurs; the nuclear envelope and nucleolus disappear; the spindle forms. This is the longest stage of meiosis.
• Metaphase I: bivalents line up at the equator. Spindle fibres from one pole attach to one homologue and fibres from the other pole to its partner.

• Anaphase I: homologous chromosomes separate and move to opposite poles. The centromeres do not divide, so each chromosome still has two chromatids.
• Telophase I: the nuclear envelope and nucleolus may re-form; cytokinesis produces two cells (a dyad), each haploid.

NCERT The five substages of prophase I (NCERT)

NCERT divides the long prophase I into five substages. These are not required by the IB guide but are tested often in NEET.

1. Leptotene: chromosomes become gradually visible under the light microscope as long, thin threads; condensation continues.
2. Zygotene: homologous chromosomes start pairing, a process called synapsis, helped by a protein framework called the synaptonemal complex. The paired homologues form a bivalent (tetrad).

1. Pachytene: the four chromatids of each bivalent become clear. Recombination nodules appear, the sites where crossing over takes place between non-sister chromatids, helped by the enzyme recombinase. Pachytene is longer than leptotene and zygotene.
2. Diplotene: the synaptonemal complex dissolves and the homologues begin to separate, except at the sites of crossing over. These X-shaped points are the chiasmata. In the oocytes of some vertebrates diplotene can last for months or years.

1. Diakinesis: chiasmata move towards the ends of the chromosomes (terminalisation); chromosomes are fully condensed; the spindle is assembled; the nucleolus disappears and the nuclear envelope breaks down. This marks the move into metaphase I.

Interkinesis

Between the two divisions there may be a short pause called interkinesis. It is like a brief interphase, but there is no DNA replication, so each chromosome still has the two chromatids it had at the end of meiosis I.

Meiosis II

• Prophase II: starts soon after cytokinesis, often before the chromosomes have fully uncoiled. The nuclear envelope disappears and the chromosomes condense again.
• Metaphase II: chromosomes line up singly at the equator. Fibres from opposite poles attach to the kinetochores of the two sister chromatids.

• Anaphase II: the centromere of each chromosome splits (cohesin is cut) and sister chromatids move to opposite poles.
• Telophase II: nuclear envelopes re-form around the four groups of chromosomes; cytokinesis produces four haploid cells (a tetrad of cells).

Meiosis II is very similar to mitosis, with one difference: it starts with a haploid cell. That is why meiosis II is sometimes called the equational division of meiosis.

Meiosis as a source of variation

The four cells produced by meiosis are genetically different from one another. IB requires two sources of this variation (D2.1.11), and random fertilisation adds a third.

1. Crossing over. In prophase I, non-sister chromatids of a bivalent break at the same points and exchange equivalent sections. Where they are joined after the exchange, a chiasma is visible. Each chromosome that has crossed over carries a new combination of alleles: a recombinant chromatid. Crossing over separates alleles of linked genes (genes on the same chromosome).

2. Random orientation of bivalents (independent assortment). In metaphase I, each bivalent lines up at the equator independently of every other bivalent. Whether the maternal or the paternal homologue faces a given pole is a matter of chance. With n pairs of chromosomes there are 2ⁿ possible combinations of chromosomes in the gametes.

In humans n = 23, so random orientation alone gives 2²³ = 8 388 608 combinations in each person’s gametes. 3. Random fertilisation then combines any one of these with any one from the other parent: 2²³ × 2²³, about 70 trillion combinations, before crossing over is even counted.

Non-disjunction and Down syndrome

Non-disjunction is the failure of chromosomes to separate correctly in meiosis. It can happen in either division:

• In meiosis I, both homologues of a pair go to the same pole. All four gametes are abnormal: two have an extra copy (n + 1) and two lack that chromosome (n − 1).
• In meiosis II, the sister chromatids of one chromosome go to the same pole in one of the two cells. Two gametes are abnormal (n + 1 and n − 1) and two are normal (n).

If a gamete with an extra chromosome 21 (24 chromosomes) is fertilised by a normal gamete (23), the zygote has 47 chromosomes, with three copies of chromosome 21. This trisomy 21 causes Down syndrome. Features can include learning difficulties, characteristic facial features, short stature and a higher risk of heart defects. The risk of non-disjunction rises with the age of the mother, especially after about 35, which is linked to the long time oocytes spend arrested in prophase I.

A gamete missing a chromosome gives a monosomy (45 chromosomes) after fertilisation. Monosomy of an autosome is not viable; the only viable human monosomy is 45,X (Turner syndrome).

Significance of meiosis

• Keeps the chromosome number of a species constant from generation to generation in sexually reproducing organisms, by halving it before fertilisation doubles it.
• Produces genetic variation through crossing over, random orientation of bivalents and (with fertilisation) random combination of gametes.
• Variation is the raw material for natural selection and evolution.
• Produces gametes in animals and spores in plants.

5 Cell cycle regulation: cyclins, CDKs and checkpoints

Syllabus link: AHL D2.1.15 Control of the cell cycle using cyclins; links to D2.1.16 (cancer). NCERT does not cover cyclins in detail.

AHL The cell cycle must be controlled. A cell should divide only when it is large enough, when its DNA has been copied correctly and when the body needs more cells. This control is carried out by proteins whose amounts rise and fall during each cycle, and by checkpoints where the cell checks that it is ready to move on.

Cyclins and cyclin-dependent kinases

• Cyclins are a family of regulatory proteins whose concentration rises and falls during the cell cycle. Different cyclins peak at different stages.
• Cyclin-dependent kinases (CDKs) are enzymes that add phosphate groups to target proteins (phosphorylation), switching them on or off. Their concentration stays roughly constant.
• A CDK is inactive on its own. When the right cyclin reaches a threshold concentration, it binds to the CDK and activates it.
• The active cyclin–CDK complex phosphorylates proteins that carry the cell past a checkpoint, for example proteins needed for DNA replication or for nuclear envelope breakdown and spindle formation.
• The cyclin is then broken down, so the CDK becomes inactive again and the next cyclin takes over. This keeps the cycle moving in one direction.

For example, the M cyclin (cyclin B) builds up through S and G₂. When it passes its threshold, cyclin B–CDK1 (historically called MPF, maturation- or mitosis-promoting factor) triggers condensation of chromosomes, breakdown of the nuclear envelope and assembly of the spindle. At the metaphase to anaphase transition APC/C tags cyclin B for destruction, the CDK switches off and the cell can complete mitosis and cytokinesis.

Checkpoints

• G₁ checkpoint (G₁/S, also called the restriction point): is the cell large enough, are nutrients and growth factors present, and is the DNA undamaged? If not, the cell pauses or enters G₀.
• G₂ checkpoint (G₂/M): has all the DNA been replicated, and has any damage been repaired? Only then can the cell enter mitosis.
• Spindle checkpoint (metaphase or M checkpoint): are all chromosomes attached to spindle fibres from both poles? Anaphase is delayed until they are, which protects against non-disjunction.

If damage cannot be repaired, the cell may be destroyed by apoptosis (programmed cell death). The protein p53, sometimes called the ‘guardian of the genome’, detects DNA damage and stops the cycle at G₁ so that the DNA can be repaired, or triggers apoptosis if it cannot.

Signals from outside the cell

Cells also respond to their surroundings. Growth factors released by other cells (for example after a wound) stimulate cells to make cyclins and pass the G₁ checkpoint. Normal cells also show contact inhibition: when they touch neighbouring cells on all sides, they stop dividing. Cancer cells have lost this property (section 7).

6 Mitosis vs meiosis: comparing the two kinds of cell division

Syllabus link: D2.1.4 Roles of mitosis and meiosis in eukaryotes; D2.1.9 Meiosis as a reduction division; NCERT 10.3, 10.5

Mitosis and meiosis both divide a nucleus, both use a spindle of microtubules and both follow one round of DNA replication. They differ in what happens to homologous chromosomes, in the number of divisions, and in the number and kind of cells produced.

7 Cancer: when the cell cycle goes out of control

Syllabus link: AHL D2.1.16 Consequences of mutations in genes that control the cell cycle; AHL D2.1.17 Differences between tumours (including the mitotic index); NCERT 10.3 (link)

In a healthy body, cells divide only when they need to. Cancer is a group of diseases in which cells divide uncontrollably because the genes that control the cell cycle have been damaged. The mass of cells formed by this uncontrolled cell division is a tumour.

Oncogenes and tumour suppressor genes

AHL Two groups of genes control the cell cycle, and mutations in either group can lead to cancer:

• Proto-oncogenes code for proteins that stimulate cell division, such as growth factors, their receptors and cyclins. A mutation can turn a proto-oncogene into an oncogene, which is permanently ‘switched on’, so the cell divides even without a signal. Only one mutated copy is needed (the mutation acts like an accelerator stuck down).
• Tumour suppressor genes code for proteins that stop cell division or trigger apoptosis when something is wrong, such as p53 and the retinoblastoma protein (Rb). If both copies are inactivated by mutation, the brake is lost and damaged cells keep dividing.

Cancer usually needs several mutations in the same cell, in both kinds of gene. Because mutations build up over time, the risk of most cancers rises with age.

Mutagens and carcinogens

A mutagen is an agent that increases the rate of mutation. A mutagen that causes cancer is a carcinogen. Examples:

• Chemical: tar and other chemicals in tobacco smoke, asbestos fibres, benzene, some food contaminants such as aflatoxins.
• Radiation: ultraviolet (UV) light from the Sun (skin cancer), X-rays and gamma rays, radiation from radioactive materials such as radon gas.
• Biological: some viruses, such as human papillomavirus (HPV, cervical cancer) and hepatitis B virus (liver cancer).

Mutations can also arise spontaneously, through errors in DNA replication, and some mutations are inherited (for example in the BRCA1 and BRCA2 tumour suppressor genes).

Benign and malignant tumours

• The tumour where the cancer starts is the primary tumour.
• Metastasis is the spread of cancer cells from the primary tumour to other parts of the body, through the blood or lymphatic system.
• A tumour formed at a new site by cells that have spread is a secondary tumour. It is made of the same type of cell as the primary tumour: breast cancer that spreads to the lung is still breast cancer.

Normal cells show contact inhibition: they stop dividing when they touch their neighbours. Cancer cells have lost contact inhibition, so they pile up into a mass, and many also lose the ability to stick to each other, which lets them break away and spread.

The mitotic index

The mitotic index is the proportion of cells in a tissue that are in mitosis at a given moment. It is a measure of how fast cells in the tissue are dividing:

Mitotic index = number of cells in mitosis ÷ total number of cells observed

Cells in prophase, metaphase, anaphase and telophase are counted as ‘in mitosis’; cells in interphase are not. The result can be given as a decimal or as a percentage. A high mitotic index shows rapid cell division. Doctors use it to grade tumours: a malignant tumour usually has a much higher mitotic index than the normal tissue around it, and a falling mitotic index during treatment suggests the treatment is working. Many anti-cancer drugs and radiotherapy target dividing cells for this reason.

Worked example: calculating a mitotic index

1. Count the cells in mitosis. In the field of view above: prophase 4 + metaphase 2 + anaphase 2 + telophase 1 = 9 cells.
2. Count all the cells. 9 in mitosis + 39 in interphase = 48 cells.
3. Divide. Mitotic index = 9 ÷ 48 = 0.1875.
4. Round sensibly. Mitotic index = 0.19 (2 significant figures), or 18.75% ≈ 19%.
5. Interpret. About one cell in five is dividing: this is a region of rapid growth (the meristem near the root tip).

Estimating time in each phase. If the cells are dividing at random, the proportion of cells in a phase is the same as the proportion of the cell cycle spent in that phase. If this cell cycle takes 24 hours, time in mitosis ≈ 0.1875 × 24 h = 4.5 hours, and time in prophase ≈ (4 ÷ 48) × 24 h = 2 hours.

Comparing tissues. In a biopsy, 1000 cells from a tumour included 120 in mitosis, while 1000 cells from nearby normal tissue included 15. Mitotic index of tumour = 120 ÷ 1000 = 0.12; normal tissue = 15 ÷ 1000 = 0.015. The tumour cells are dividing about 8 times as often.

9 Quick check

Ten questions: six multiple choice and four short answer. Try them all before opening the answers.

1. During which phase of the cell cycle is DNA replicated?

   • A. G₁
   • B. S
   • C. G₂
   • D. Prophase

2. A cell in G₁ has 2C DNA and 2n = 14. What are the DNA content and chromosome number of the same cell in G₂?

   • A. 2C, 14
   • B. 4C, 14
   • C. 4C, 28
   • D. 2C, 28

3. Which event occurs in anaphase I of meiosis but not in anaphase of mitosis?

   • A. Sister chromatids separate
   • B. Homologous chromosomes separate
   • C. Centromeres split
   • D. The nuclear envelope re-forms

4. In which substage of prophase I does crossing over take place?

   • A. Leptotene
   • B. Zygotene
   • C. Pachytene
   • D. Diakinesis

5. Which statement about cyclins is correct?

   • A. Cyclins are enzymes that phosphorylate proteins
   • B. Cyclin concentration stays constant through the cycle
   • C. Cyclins activate cyclin-dependent kinases
   • D. Cyclins are only found in cancer cells

6. Cytokinesis in a plant cell involves:

   • A. a contractile ring of actin and myosin
   • B. a cleavage furrow growing inwards
   • C. Golgi vesicles fusing to form a cell plate
   • D. the formation of asters

7. State two differences between benign and malignant tumours.

8. Explain how non-disjunction can lead to Down syndrome.

9. A root tip field of view has 400 cells, of which 36 are in mitosis. Calculate the mitotic index and state what a higher value in a tumour would show.

10. Outline two ways in which meiosis generates genetic variation.

10 Glossary