The Cell Cycle, Cell Division 2023 RF.pptm

The Cell Cycle, Cell Division and its Control Dr Robert Formosa Learning Objectives • Describe the main features of the cell cycle • Describe the mechanisms and biological functions of mitosis and meiosis • Discuss the role of genes in coordinating the cell cycle • Give examples of human diseases...

The Cell Cycle, Cell Division and its Control Dr Robert Formosa Learning Objectives • Describe the main features of the cell cycle • Describe the mechanisms and biological functions of mitosis and meiosis • Discuss the role of genes in coordinating the cell cycle • Give examples of human diseases associated with mutations in these genes Cell Division • All life starts as a single cell. • Process by which one cell replicates itself completely. 2n = 46 chromosomes (diploid) • Why is cell division important: n = 23 chromosomes (haploid) • Evolution of life • Cell repair/replacement • Genetic variation • Growth • Two types of Cell division: • Mitosis and meiosis Tissues Gametes Mitosis and Meiosis Some terms Chromatids: Each of the two thread-like strands into which a chromosome divides longitudinally during cell division. Each contains a double helix of DNA. Homologous chromosomes: A pair of chromosomes having the same gene sequences, each derived from one parent. Learning Objectives • Describe the main features of the cell cycle • Describe the mechanisms and biological functions of mitosis and meiosis • Discuss the role of genes in coordinating the cell cycle • Give examples of human diseases associated with mutations in these genes The Cell Cycle The cycle through which all cells go through to divide and form other cells. The process of cell division is broadly divided into three phases: 1. The interphase, composed of 3 sub-phases: a. G1 phase b. S phase, during which DNA replication occurs c. G2 phase 2. The mitotic phase (M-phase), when the nucleus divides, and 3. Cytokinesis, during which the cytoplasm is divided between the two daughter cells. The timing of each phase determines the rate at which the cell reproduces and will influence the rate of tissue growth. 4N 2N The Cell Cycle Made up of 4 phases: - G0 phase – most cells are stuck in this phase when they stop dividing but can escape Go and enter G1 to divide again 1. G1 phase – normal growth phase with preparation for DNA synthesis 2. S (synthesis) phase – DNA is synthesized and duplicated (once cell enters the S phase it is committed to divide) 3. G2 phase – cell prepares for cell division 4. M (mitosis/meiosis) phase – proper cell division occurs The G phases • Gap (Growth) phases • Cell spends most time in these phases • Cells that do not divide (most somatic cells) enter G0 phase but can re-enter the normal cell cycle (cancer) • No synthesis of DNA • Allows cell time to monitor the environment (internal and external) to make sure that conditions are suitable before progressing to the next phase • During the G phases, the cell undergoes important ‘checkpoints’ The S phase • Synthesis phase • DNA is duplicated: 23 (2N)  46 (4N) Duplicated The M phase • Mitosis – cell divides into 2 identical cells • Made up of 4 stages: • • • • Prophase Pro/Metaphase Anaphase Telophase • Final phase is cytokinesis (splitting of cytoplasm in 2) Learning Objectives • Describe the main features of the cell cycle • Describe the mechanisms and biological functions of mitosis and meiosis • Discuss the role of genes in coordinating the cell cycle • Give examples of human diseases associated with mutations in these genes Mitosis : Prophase During Prophase: Chromoso 1. Nucleolus disappears 2. chromatin condenses into well defined chromosomes (two identical chromatids (sister chromatids) linked by centromere. 3. cytoplasmic microtubules disassemble 4. mitotic spindle begins to form outside the nucleus between a pair of separating centrosomes. Centrosomes (composed of 2 centrioles) me (made up of 2 sister chromatids ) Mitotic spindle Mitosis : Prometaphase & Metaphase During Pro-metaphase: 1. Nuclear envelope dissolves 2. Microtubules form a radiating array 3. Microtubules attach to the centromere of the chromosomes at the kinetochore 4. Centrosome move towards opposing ends of the cell During Metaphase: 5. Chromosomes are aligned by the mitotic spindle towards the centre Kinetochore: 2 regions: – inner binds to centromere; composed of specialized nucleosomes and are present throughout cell cycle outer binds microtubules and it formed only during cell division Mitosis : Anaphase During Anaphase: 1. Mitotic spindle microtubules start to retract 2. This pulls the sister chromatids apart through their kinetochores 3. Spindles move further apart towards the poles Most critical part of mitosis which ensures equal distribution of chromosomes between cells Cohesin - protein complex that regulates the separation of sister chromatids during cell division. They hold chromatids together until anaphase. Cohesinopathies – leads to extra or less chromosomes due to non-dysjunction – ex. Down’s synd., Robert’s synd., Cornelia de Lange synd. Mitosis : Anaphase During Anaphase: 1. Mitotic spindle microtubules start to retract 2. This pulls the sister chromatids apart through their kinetochores 3. Spindles move further apart towards the poles Most critical part of mitosis which ensures equal distribution of chromosomes between cells Cohesin - protein complex that regulates the separation of sister chromatids during cell division. They hold chromatids together until anaphase. Cohesinopathies – leads to extra or less chromosomes due to non-dysjunction – ex. Down’s synd., Robert’s synd., Cornelia de Lange synd. Mitosis : Telophase & Cytokinesis During Telophase: 1. Separated, uncoiled, chromosomes reach the poles of the mitotic spindle 2. Centrioles/centrosome and mitotic spindle begin to disappear 3. New nuclear envelope starts to form During Cytokinesis: 4. Contractile ring formed from actin and myosin pinches the cell until it splits (cleaves) into 2 daughter cells 5. Cell membrane invaginates in the centre of the cell at right angles to the long axis of the mitotic spindle to form a cleavage furrow 6. Furrow deepens until only a narrow neck of cytoplasm joins the two daughter cells. Mitosis : Summary https://www.youtube.com/watch?v=L61Gp_d7evo Meiosis Process by which gamete cells are produced (sperm and ova) containing half number of unpaired chromosomes (haploid/2n) Divided in 2 phases: Meiosis I (2n to n) Prophase I, Metaphase I, Anaphase I & Telophase I and Meiosis II Prophase II, Metaphase II, Anaphase II & Telophase II gamete release Errors in meiosis resulting in aneuploidy (abnormal number of chromosomes) are the leadin known cause of miscarriage and the most frequent genetic cause of developmental disabilities Meiosis – Prophase I Same as Prophase in mitosis, cell starts out by replicating its chromosomes forming pairs of homologo chromosomes. Stages of prophase I: 1. Chromosomes condense 2. Homologous chromosomes align at the centre of the cell 3. Homologous chromosomes are joined at points called chiasmata forming a bivalent. 4. Crossing over or recombination can occur at chiasma 5. Nuclear envelope breaks down. Crossing over/ recombination This is the main source of genetic variation between generations. This produces a unique combination of genes in the resulting zygote. Also independent assortment (random allocation of chromatids to each gamete during metaphase I) increases genetic variation. Chiasmata is the point of contact, the physical link, between two chromatids belonging to homologous chromosomes. At a given chiasma, an exchange of genetic material can occur between both chromatids, what is called a chromosomal crossover, and occurs in meiosis but not mitosis. Meiosis: Metaphase I & Anaphase I Similar to mitosis. Steps occurring: 1. Nuclear envelope completely dissolves. 2. Pairs of homologous chromosomes move to centre of cell and face opposite sides of the spindle (this process is random and is a source of final genetic variation in gametes) Anaphase I – chromosomes separate 3. Kinetochore microtubules shorten and pull chromosomes in opposite directions. 4. Sister chromatids remain attached at this stage so each pole gets two copies of the same chromosome (variation can occur due to crossing over during prophase/metaphase) Metaphase I Anaphase I Meiosis: Telophase I & Cytokinesis I Again similar to mitosis. Steps occurring at telophase I: 1. microtubules that make up the spindle network disappear. 2. new nuclear membrane surrounds each haploid set 3. chromosomes uncoil back into chromatin. Sister chromatids remain attached. Cytokinesis I: 1. Cytoplasm splits between the middle of the cell creating two daughter cells. Cells may enter a period of rest known as interkinesis or interphase II. No DNA replication occurs during this stage Meiosis II The 2nd phase of meiosis is more similar to mitosis. Major difference: no further DNA replication prior to cell division, therefore DNA content is halved in the 2 daughter cells (haploid gametes) https://www.youtube.com/watch?v=nMEyeKQClqI Cell division: what can go wrong!? Non- disjunction: Can occur at meiosis I or II leading to chromosomal aneuploidy (varying number of chromosomes in a cell – 45 or 47) Cell division: what can go wrong!? Non- disjunction: Can occur at meiosis I or II leading to chromosomal aneuploidy (varying number of chromosomes in a cell – 45 or 47) Trisomy 21 – Down Syndrome Other common aneuploidies: Non-autosomal: Turner syndrome (XO) , Kleinfelter syndrome (XXY) Autosomal: Warnaky syndrome (trisomy 8) – fatal in first trimester Patau syndrome (trisomy 13) - fatal in first month/year Edwards syndrome (trisomy 18) – often fatal in utero, or within first weeks/months Learning Objectives • Describe the main features of the cell cycle • Describe the mechanisms and biological functions of mitosis and meiosis • Discuss the role of genes in coordinating the cell cycle • Give examples of human diseases associated with mutations in these genes Control of the Cell Cycle In order to prevent cells from dividing uncontrolled or to initiate cell division when appropriate, the cell cycle is strictly regulated. Cell size, DNA damage, DNA replication Chromosome attachment to spindle Cells must receive specific signals or triggers to initiate cell division. Specific cell cycle checkpoints are responsible for driving or stopping the cell cycle. This is further regulated by specific genes and proteins that have to be expressed and activated in order for the cell cycle to progress. If errors are detected at specific checkpoints, the cell cycle can either be stopped Growth factors, nutrients, cell size, DNA damage Cyclins, CDKs, CDKIs The cell cycle is regulated mainly at the molecular level by a number of proteins, most important of which are: 1. Cyclins 2. Cyclin-dependant kinases (CDKs) 3. Cyclin-dependant kinase inhibitors (CDKIs) Cyclin proteins bind to CDKs and regulate their ability to phosphorylate other proteins that control cell division/cycle. Cyclins, CDKs, CDKIs CDKIs are also important in regulating cyclinCDK complexes to prevent cells from entering the cell cycle. Therefore the expression levels between CDKs and CDKIs keeps the balance between a cell progressing in the cell cycle or not. CDKI proteins (p16, p21 and p27) primarily act to block the entry into the cell cycle and the G1/S transition P53 = Guardian of the Genome blocks progression of cell cycle Synthesizes P21 which inhibits CDK2 Dysfunction of P53 = CANCER Important tumour suppressor gene! Learning Objectives • Describe the main features of the cell cycle • Describe the mechanisms and biological functions of mitosis and meiosis • Discuss the role of genes in coordinating the cell cycle • Give examples of human diseases associated with mutations in these genes Retinoblastoma Retinoblastoma (Rb): - rare form of cancer that rapidly develops from the immature cells of a retina. - most common in young children. - Often children have genetic defects in the retinoblastoma gene. - One of the first genes directly related to cancer Retinoblastoma protein (Rb) is an tumour suppressor that is generally switched on by p53/p21 ands switched off by cyclin E/CDK. Normally, Rb prevents DNA synthesis and replication, by binding the E2F protein and preventing it from driving DNA replication forward. Therefore, knocking out a tumour suppressor leaves cell division to more forward uncontrolled  CANCER! Stopping cell division (cancer): Chemotherapy Different chemical agents can disrupt the cell cycle at different stages. Generally divided in different classes of drugs depending on their mode of action: •Anti-mitotics • Traditional chemotherapy drugs • Not selective will affect any dividing cell •Biologicals • Selective drug that target proteins that are essential for their growth • Monoclonal antibodies •Anti-hormonal drugs • If tumour is hormone –driven (ex. androgens or estrogen), these block either their production or their receptors Anti-mitotic drugs Most chemotherapy drugs that block mitosis actually work on the mitotic spindle and inhibit its assembly, called anti-microtubule agents. Vinca alkaloids and taxanes are the two main groups of anti-microtubule agents. This leads to a block in the cell cycle, causing cells to enter apoptosis and die. Other mitotic blockers: - Inhibitors of mitotic kinases • CDK inhibitors interfering with G1/S • Aurora kinase inhibitors interfering with centriole/centrosome function - Inhibitors of kinesins Microtubule motor proteins - Other targets Cohesin and kinetochore Summary • Cell division • Mitosis vs Meiosis • The Cell Cycle • Mitosis: • • • • Prophase Metaphase Anaphase Telophase • Meiosis – genetic variation – crossing over & independent assortment • Control of the cell cycle: CDK, check point inhibitors, cyclins • Diseases associated with cell division: cancer • Chemotherapy: stopping uncontrolled cell division