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Cell Cycle 1 – The Cell Cycle Anil Chopra 1. Describe the cell cycle in terms of the named phases (G0, G1, G2, S, M) and explain what these mean in terms of protein and DNA synthesis. 2. Identify (or sketch or describe) the named stages of mitosis. 3. Explain the importance of checkpoints in controlling progression through the cell cycle, and give examples of external factors which provide signals allowing cells to pass these checkpoints and enter cell division. 4. Give examples of the different rates of cell division found for cells in different tissues and under different physiological and pathological conditions. 5. Describe the way the cell cycle allows decision making about whether a cell divides, differentiates or undergoes programmed cell death (apoptosis). Cells divide at different rates depending on: - Whether they are embryonic or adult cells - How complex the system is - The necessity for renewal - State of differentiation - If they are tumour cells The Cell Cycle Process 2 main phases: Interphase – the cell is metabolising, duplicating its organelles, and synthesising proteins. M-Phase / Mitosis – where the nucleus divides and the cell divides by cytokinesis. It is also the most vulnerable period in the cell cycle as cells are most easily killed by heat/radiation, DNA damage cannot be repaired and gene transcription is unable to take place. Mitosis is essential because: - premature mitosis results in cell death - most tumours are aneuploid (abnormal chromosome numbers) and chromosomal instability - changes in the regulators of the cell cycle are found in tumour cells - attacking the machinery that regulates chromosome segregation is one of the most successful anti-cancer strategies in clinical use. M phase - Mitosis Interphase: G0 - cell cycle machinery dismantled G1 phase (Gap) - Decision point S phase - Synthesis of DNA/protein G2 phase (Gap) - Decision point S Phase Where replication of DNA and organelles occurs. The time of protein synthesis – initiation of translation and elongation increased, capacity is also increased. Mitosis Prophase The replicated chromosomes condense. They migrate to opposite sides of the nucleus. The mitotic fibres form between then 2 centrosomes o Consists of two centrioles (barrels of nine triplet microtubules) o Is the primary microtubule organizing centre (MTOC) kinetochore centromere Sister chromatids Condensed chromosomes form: 2 sister chromatids, each with a kinetochore Spindle fibers form: o Radial microtubule arrays from around the centrosome. o These arrays meet up. o Polar microtubules form between them. o These are all in a dynamic state. Metaphase The chromosomes align along the equator of the spindle. Early Prometaphase Break down of the nuclear membrane. Microtubules grow and shrink in aster (the spindles around the centrosomes). The chromosomes attach to the spindles via the kinetochore – at the centromere part of the chromosome Late Prometaphase Microtubules from opposite poles are captured by sister kinetochores causing the chromosomes attached to each pole to congress to the middle. Chromosomes slide rapidly towards the centre along microtubules. The microtubules are in a DYNAMIC state. Anaphase The paired chromatids are separated forming two daughter chromosomes. This is done by the breakdown of “cohesion” – a molecule that holds the chromatids together. The daughter chromatids are pulled to the opposite spindle poles by a process called “treadmilling”. o Tubulin monomers are added to the plus + end of the microtubule. o The same number of monomers is lost at the minus – end. o This results in the movement of the kinetochore attached to the microtubules. Telophase Daughter chromosomes arrive at the spindle. Nuclear envelope reassembles at each pole. Contractile ring of actin and myosin filaments forms. Mitotic Checkpoints At various stages in the cell cycle – the chromosomes are checked for abnormalities: Spindle Assembly Checkpoint: Senses completion of chromosome alignment and spindle assembly (monitors kinetochore activity) and takes place during Prometaphase and metaphase. It requires centromere protein E (CENP-E) and BUB protein kinases. They dissociate from the kinetochore when they attach to the spindle. If this checkpoint fails, aneuploidy can result. This is because, one of the chromosomes will fail to dissociate. Aneuploidy can also result from mis-attachment of microtubules to kinetochores. This can result in one of three kinds of attachment: Amphelic: normal attachment, each microtubule to a kinetochore from different centromeres. Syntelic: both kinetochores are attached to microtubules from the same centromere, which results in both sister chromatids going to the same pole. Merotelic: more than one microtubule attaches to the same kinetochore. This results in chromosome loss during cytokinesis. Aneuploidy can also result form aberrant mitosis: This is where the cell cycle, either at the point of spindle fibre attachment, or during cytokinesis. Anti-Cancer Therapy can involve Inducing Gross Chromosome Mis-segregations Taxanes & Vinca Alkaloids: mitotic inhibitors. Essentially they “freeze” mitosis because they alter the dynamics of microtubules to produce un-attached kinetochores. At the end of mitosis cells can either enter G0 or G1 depending on whether or not growth factors are present. In G0 the cell is not dormant, it continues to perform its role. In G1, the longest and most variable phase of the cell cycle, the cell literally grows, protein and organelle synthesis occurs whilst growth factors are present (they have to be continually present). There is a check-point at the end of G1. In G2 there is a gap between DNA replication and mitosis. If the cell is not big enough, then the phases are delayed i.e. mitotic arrest. When DNA is slightly damaged cell cycle arrest can occur (i.e. G2 is longer), but if it is severely damaged, then apoptosis occurs.