Cell Cycle PDF

PHA3110 – Molecular Biology, Q3 - 2024 Ellie Nguyen, PhD CELL CYCLE  Learning objectives I. Describe different phases of the cell cycle II. Describe key events occurring in the different phases of the cell cycle III. Describe mitosis and the key pha...

PHA3110 – Molecular Biology, Q3 - 2024 Ellie Nguyen, PhD CELL CYCLE  Learning objectives I. Describe different phases of the cell cycle II. Describe key events occurring in the different phases of the cell cycle III. Describe mitosis and the key phases of mitosis IV. Identify antimitotic agents and describe their mechanisms of action Cell Cycle A sequence of intracellular events that lead to the production of two genetically identical daughter cells.  Pass along the genetic code All living organism regardless of the complexity are products of repeated rounds of cell division. Unicellular organisms undergo cell division to reproduce themselves called as binary fission. Multicellular organisms undergo cell division to grow or repair or replace dead cells.  Millions of human cells divide every second Bruce Alberts et al., Molecular Biology of The Cell, 6e, © 2014  Cell Cycle It is important that two genetically identical cells are produced from cell division. This is achieved by 3 major checkpoints  G1 check point: before entering S phase  G2 check point: before entering M phase  Metaphase (M) check point: during division Checkpoints ensure  Orderly transition through the cell cycle  High fidelity DNA replication  Error free repair if DNA damage Bruce Alberts et al., Molecular Biology of The Cell, 6e,  Correct chromosome segregation © 2014 Mutation can allow cells to grow excessively or to avoid cell death (apoptosis). As cells divide, Problems – failure of checkpoints mutation can be transferred to progeny and  Aneuploidy (one or more extra or missing accumulation of these cells leads to cancers- chromosomes in a cell or organism) One reason why it takes a long time for tumors  Abnormal DNA (mutation) to develop  Eukaryotic Cell Cycle  Consists of 4 main phases: G1 -> S -> G2 -> M  Growing cell cycle includes 2 main stages: 1. A dividing phase called the mitotic (M) phase chromosome segregation and cell division, with two major events: Mitosis: division of nucleus Cytokinesis: division of cytoplasm 2. A nondividing phase called interphase, including G1, Bruce Alberts et al., Molecular Biology of The Cell, 6e, S, G2 phases: © 2014 S phase – synthesis phase: chromosome duplication G1 phase – first gap/growth: between M & S phase G2 phase – second gap/growth: between S & M phase  Interphase: G phases During the gap phases : organelles replicate, and additional cytoplasm is made in preparation for either S or M phases. Gap phases allow the cell to:  Duplication of the organelles and macromolecules  Monitoring of intracellular and extracellular environment and signals G1 phase – first gap: growth & metabolism phase Go G2 phase – second gap – growth of structural elements. Go – resting phase – mature muscle cells and neurons remain in resting Go phase outside of the active cell cycle. Freeman et al., Biological Science with Masteringbiology, 5e, © 2013  Interphase: G phases G1 phase – most of cell life, for growing, making proteins and organelles, more critical and last longer than G2 which prepares for mitosis and making microtubules. Varying length based mostly on external environmental conditions If environment is favorable  Passes through a checkpoint (commitment point) If environment is unfavorable Go  G1 delay or G0  G0: cell cycle arrest Resting/Quiescent/Senescent cell Freeman et al., Biological Science with Masteringbiology, 5e, © 2013  Interphase: S phase – chromosome replication The stage in which DNA replication occurs is called the synthesis (S) phase Each of the DNA copies in a replicated chromosomes is called as sister chromatids Chromatids are joined together at a specialized region of the chromosome called the centromere Packaging proteins must also be replicated S phase in a typical mammalian cell  Lasts about 10 - 12h, 50% of cell cycle  At any point in time 30 - 40% of cell in a population Freeman et al., Biological Science with Masteringbiology, 5e, © 2013  Mitosis (M) phase Mitosis is nucleus division of somatic cells, and usually accompanied by cytokinesis for cytoplasm division The purpose of mitosis is to distribute chromosomes to daughter cells during cell division Each chromosome is replicated before mitosis At the end of mitosis:  The division of replicated chromosomes equally Freeman et al., Biological Science with Masteringbiology, 5e, © 2013  Formation of two daughter nuclei with identical chromosomes and genes  Mitosis (M) phase Mitosis or M phase is relatively fast, within an hour in some mammalian cells. M phase is a continuous process with five subphases based on specific events (PPMAT): Prophase Prometaphase Metaphase Anaphase Telophase Bruce Alberts et al., Molecular Biology of The Cell, 6e,  Prophase In M phase  During prophase, chromosomes form rigid rods called sister chromatids:  joined at the centromere by a protein complex called cohesin  needed to prevent damage to chromatids  often the first indication of the M-phase Outside the nucleus, the microtubule-organizing center is formed as a centrosome that contains a pair of centrioles and spindle apparatus Abrupt increase in activity of mitotic cyclin dependent kinase (M-Cdk) essential for initiating and coordinating the events of mitosis, such as chromosome condensation, spindle assembly, and nuclear envelope breakdown. Freeman et al., Biological Science with Masteringbiology, 5e, © 2013  Prometaphase In M phase During prometaphase, under the influence of M-Cdk:  The nuclear envelop breaks down  The nucleolus disappears Kinetochore microtubules attach to one of the sister chromatids of each chromosome Attachment occurs in the centromere region at the kinetochore. Active movement of each chromosome begins towards the spindle equator.  Metaphase In M phase During metaphase, under the influence of M-Cdk:  Formation of the mitotic spindle is completed Metaphase lasts for about half the duration of mitosis Motor proteins on the kinetochore microtubules:  Pull each chromosome in opposite directions  Causing the replicated chromosomes or sister chromatids to line up in the middle of the cell at the spindle equator or metaphase plate. Freeman et al., Biological Science with Masteringbiology, 5e, © 2013  Sister chromatids separate; one chromosome copy goes to each daughter nucleus. Sister Kinetochore chromatids Centrioles Kinetochore Centrosomes Chromosomes Early spindle apparatus Polar microtubules microtubules Astral microtubules 1. Interphase: After 2. Prophase: Chromosomes 3. Prometaphase: Nuclear 4. Metaphase: chromosome replication, condense, and spindle envelope breaks down. Chromosomes complete each chromosome is apparatus begins to form. Microtubules contact migration to middle of cell. composed of two sister kinetochores. chromatids. Freeman et al., Biological Science with Masteringbiology, 5e, © 2013  Practice Questions 1. The key cellular event during the S-phase of the cell cycle is chromosomal segregation. True or False? 2. Which phase has cell cycle resting? 3. The sister chromatids to line up in the middle of the cell at the _______.  Anaphase In M phase During anaphase:  Centromeres split sister chromatids to two identical sets of chromosomes called as daughter chromosomes  The spindle poles move apart and pulls the daughter chromosomes away from the metaphase plate in the middle  Daughter chromosomes are moving toward opposite poles of the cell Activation of the anaphase promoting complex (APC) which catalyzes:  Destruction of cohesion in sister chromatids  Inactivation of mitotic cyclin dependent kinase (M-Cdk) Freeman et al., Biological Science with Masteringbiology, 5e, © 2013  Telophase In M phase During telophase:  A new nuclear envelope begins to form around each set of chromosomes  The mitotic spindle disintegrates  The chromosomes begin to decondense Mitosis is complete when two independent nuclei have formed Division of cytoplasm begins in cytokinesis process Freeman et al., Biological Science with Masteringbiology, 5e, © 2013  NUCLEUS DIVISION Cytoplasm is divided. 5. Anaphase: Sister chromatids 6. Telophase: The 7. Cell division begins: 8. Cell division is separate into daughter nuclear envelope re- Actin–myosin ring causes complete: Two chromosomes and are pulled forms, and chromosomes the plasma membrane to daughter cells form. apart. de-condense. begin pinching in. Freeman et al., Biological Science with Masteringbiology, 5e, © 2013  Cytokinesis In M phase Cytokinesis typically occurs immediately after mitosis completion. During this process  The cytoplasm divides to form two daughter cells with identical genetic material  Each daughter cell has its own nucleus and complete set of organelles Cytoplasm is divided into two by the actin-myosin contractile ring that causes the plasma membrane to begin pinching in. Freeman et al., Biological Science with Masteringbiology, 5e, © 2013  Different Cell Types Undergo Cytokinesis Differently Cytokinesis in plants occurs  As vesicles are transported from the Golgi apparatus to the middle of the dividing cell  These vesicles fuse to form a cell plate Cytokinesis in animals and fungi occur:  When a ring of actin-myosin filaments contracts inside the cell membrane  Causing it to pinch inward in a cleavage furrow Freeman et al., Biological Science with Masteringbiology, 5e, © 2013  Antimitotic Agents Antimitotic agents are a class of drugs that interfere with the process of mitosis by targeting microtubules, usually at the metaphase-anaphase transition Microtubules are hollow polymeric tubes present in all eukaryotic cells. They form tracks for intracellular transport or movement. Microtubules are made up of tubulin polymers  Monomeric units: α- and β-tubulin dimers Microtubules are essential for:  Spindle Formation: Ensuring proper chromosome alignment and segregation.  Chromosome Movement: During metaphase and anaphase.  Antimitotic Agents Antimitotic agents are widely used in cancer treatment as chemotherapy Taxol drugs because they disrupting microtubule and inhibit cell cycle of rapidly dividing cells. They induce “mitotic arrest” and consequently cell cycle arrest  Taxanes (taxols) – Paclitaxel and Docetaxel  Vinca alkaloids – Vincristine and Vinblastine  Colchicine and Nocodazole Vinca alkaloids Colchicine Nocodazole  Taxols Taxol: Paclitaxel, Docetaxel Used in cancer chemotherapy for breast cancer MOA: stabilizing microtubules and preventing Control With Taxol their normal breakdown, which disrupts the cell division process and arrests cancer cell growth. Induce metaphase arrest Figure 16-23b,c Molecular Biology of the Cell 5th Ed(© Garland Science 2008)  Antimitotic Agents Vinca alkaloids, Nocodazole and Colchicine Vinca alkaloids MOA: binding tubulin subunits and prevent their polymerization, which disrupts the cell division process and arrests cancer cell growth. Metaphase arrest Colchicine Nocodazole Also used in various cancer chemotherapy  Summary of Cell Cycle Cell cycle results in the formation of genetically identical daughter cells  It consist of 4 main phases: G1, S, G2, (interphase) and Mitotic (M) phases  G-phases – Cell growth and assessment of environmental conditions  S-phase – DNA replication to form replicated chromosomes  M-phase – Chromosomal segregation and formation of two daughter nuclei M-phase consists of prophase, prometaphase, metaphase, anaphase, telophase, and cytokinesis The early part of the M-phase is under the control of M-Cdk  M-Cdk is inactivated in the later stages of the M-phase by the anaphase promoting complex (APC) Antimitotic agents affect microtubule assembly and dis-assembly to induce cell cycle arrest, especially inhibiting metaphase. Rapidly dividing cells or cancer cells are more sensitive to anti-mitotic agents:  Rationale for use in cancer treatment  Practice Questions 1. What is the main event in anaphase of mitosis? 2. Mitosis separates chromosomes and nuclei, and cytoplasm is divided between two daughter cells by _____ process. 3. Which phase of mitosis is inhibited by taxol?