Eukaryotic Cell Cycle PDF

# Eukaryotic Cell Cycle - Eukaryotes = cells with a definite nucleus (i.e. with a definite nuclear envelope) - Cells only divide when appropriate (asexual cycle) - Normally not dividing - Divide to replace dead or missing cells - division via an orderly sequence of events - Stimula...

# Eukaryotic Cell Cycle - Eukaryotes = cells with a definite nucleus (i.e. with a definite nuclear envelope) - Cells only divide when appropriate (asexual cycle) - Normally not dividing - Divide to replace dead or missing cells - division via an orderly sequence of events - Stimulated by growth factors - Inhibited by growth suppressors - Examples - Intestinal cells = every 3 days - Blood cells = every 3 months - Nerve cells = last for life - Embryonic cells = every 30 minutes # Eukaryotic Cycle (cont.) ## Abnormalities - If cells divide too often = cancer - If cells don't divide enough = cell death (apoptosis) - Before division, the entire genome must be replicated (copied) - cell then has two complete sets of DNA - When the cell with two sets of DNA divides into two daughter cells, each daughter has one complete set of DNA (complete genome) - Cell division includes carefully coordinated spatial & temporal events ## Different Phases - **Interphase** = cell not dividing (consists of 3 sub-phases) - **Mitotic phase** = cell busy dividing (consists of 5 sub-phases) # Eukaryotic Cycle - Diagram: https://www.ncbi.nlm.nih.gov/ - G₁ - G₂ - G₀ - Cells not actively dividing - M # Eukaryotic Cycle (cont.) ## Interphase - Long preparatory period - Cell not dividing, but may be preparing to divide - Three distinguishable sub-phases: - first gap (G₁) - synthesis (S) - second gap (G₂) ## Mitotic Phase (M) - Division & distribution of replicated genetic material to two daughter cells - Five distinguishable sub-phases: - prophase - prometaphase - metaphase - anaphase - telophase, followed by cytokinesis ## Passage through the phases controlled by three major checkpoints - Ensures that required processes are completed before cell moves to next phase - Ensures adequate resources to move to next phase # Eukaryotic Cycle - Diagram: https://www.ncbi.nlm.nih.gov/ - G₁ - G₂ - G₀ - Cells not actively dividing - M # G1-PHASE - First of the three sub-phases of interphase - G₁ = first gap phase - Not part of mitosis, but a preparatory phase - Little change visible in cell, but quite active on a biochemical level - Accumulating - Building blocks of chromosomal DNA - Associated proteins - Energy reserves - G₀ - If daughter cell from mitosis does not immediately enter G₁, cell is in a quiescent stage - not actively preparing to divide - E.g. cells that rarely divide, such as cardiac muscle & nerve cells - Sometimes temporary, until an external signal triggers onset of G₁ # G1-PHASE (cont.) ## Biochemical events during G₁ - Chromosomes are semi-condensed - Double-stranded DNA wraps around histone proteins = forms nucleosomes - Nucleosomes coil together = forms a chromatin fibre ## Events controlled by positive & negative regulators of growth and division: - p53 inhibits the cell cycle in G₁ = controls rate of biochemical processes - If p53 is inactivated due to mutation = loss of cell cycle control - Signals such as growth factors or stimulation of hormone receptors stimulate growth & division # Eukaryotic Cycle - Diagram: https://www.ncbi.nlm.nih.gov/ - G₁ - G₂ - G₀ - Cells not actively dividing - M # S-PHASE (DNA REPLICATION) - Second of the three sub-phases of interphase - DNA still in semi-condensed chromatin formation (formed during G₁) - S-phase = synthesis phase - DNA is replicated & an exact copy of each chromosome in synthesized. - Every chromosome is replicated (every chromosome then has a sister chromatid) - Sister chromatids = two exact copies of a chromosome (attached to each other at the centromere region) - DNA replication requires various enzymes: - **DNA topoisomerases** - "k" enzyme - Relax DNA from its supercoiled nature, by temporarily cutting the backbone of one or both DNA strands - If defective = over-winding, super-twisting or tangling of DNA (DNA cannot be replicated if still coiled) # Eukaryotic Cycle - Diagram: https://www.ncbi.nlm.nih.gov/ - G₁ - G₂ - G₀ - Cells not actively dividing - M # S-PHASE (cont.) ## Enzymes (continued): - **Helicases** (helix destabilising enzyme) - Follow behind the topoisomerases (which break the DNA backbone) & unwinds a piece of the DNA to create a replication fork. - **DNA polymerases** - Dedicated to copying DNA - synthesise sister chromatids for each chromosome. - Each DNA strand is made up of four types of nucleotides (adenine, cytosine, guanine & thymine) (A, C, G & T) - Each strand of DNA serves as a template for synthesis of its sister chromatid (A-T and G-C pairing) - Cell now has twice the amount of DNA it needs - Numerous other enzymes not discussed here # Eukaryotic Cycle - Diagram: https://www.ncbi.nlm.nih.gov/ - G₁ - G₂ - G₀ - Cells not actively dividing - M # S-PHASE (summary) - **Topoisomerase** cuts DNA & relaxes super coiled structure - **Helicase** unwinds the double strands - **Polymerase** synthesises a copy of each strand - Diagram: Natalia Pellegata, Heimholtz Zentrum München - Replicated DNA - Replication fork - Helicase - DNA polymerase - Replicated DNA # Eukaryotic Cycle - Diagram: https://www.ncbi.nlm.nih.gov/ - G₁ - G₂ - G₀ - Cells not actively dividing - M # G2-PHASE - Third of the three sub-phases of interphase - **Second gap phase** - starts when S-phase (DNA replication) is completed - Replenishing of energy stores - Synthesis of proteins necessary for chromosome manipulation - Duplication of cell organelles - Preparation of resources for the mitotic spindle - Additional cell growth in some cases # Eukaryotic Cycle - Diagram: https://www.ncbi.nlm.nih.gov/ - G₁ - G₂ - G₀ - Cells not actively dividing - M # M-PHASE & CYTOKINESIS - **Prophase** - Chromosomes condense and become visible - Spindle fibers emerge from the centrosomes. - Nuclear envelope breaks down. - Centrosomes move toward opposite poles. - **Prometaphase** - Chromosomes continue to condense. - Kinetochores appear at the centromeres. - Mitotic spindle microtubules attach to kinetochores. - **Metaphase** - Chromosomes are lined up at the metaphase plate. - Each sister chromatid is attached to a spindle fiber originating from opposite poles. - **Anaphase** - Centromeres split in two. - Sister chromatids (now called chromosomes) are pulled toward opposite poles. - Certain spindle fibers begin to elongate the cell. - **Telophase** - Chromosomes arrive at opposite poles and begin to decondense. - Nuclear envelope material surrounds each set of chromosomes. - The mitotic spindle breaks down. - Spindle fibers continue to push poles apart. - **Cytokinesis** - Animal cells: a cleavage furrow separates the daughter cells. - Plant cells: a cell plate, the precursor to a new cell wall, separates the daughter cells. - Diagram: - Credit "diagrams", modification of work by Mariana Ruiz Villareal: credit "mitosis micrographs": modification of work by Roy van Heesbeen; credit "cytokinesis micrograph"; modification of work by the Wadsworth Center, NY State Department of Health; scale-bar data from Matt Russell # MITOSIS - Diagram: - Credit "diagrams", modification of work by Mariana Ruiz Villareal: credit "mitosis micrographs": modification of work by Roy van Heesbeen; credit "cytokinesis micrograph"; modification of work by the Wadsworth Center, NY State Department of Health; scale-bar data from Matt Russell # M-PHASE & CYTOKINESIS - Mitosis = stage in cell cycle where replicated genetic material is distributed (separated) to two daughter cells - Previous - Five distinguishable sub-phases (see next slide) - Nuclear envelope disappears - The double set of genetic material is divided in two - Chromosomes migrate to the spindle equator to form the "Metaphase Plate" - Each set of genetic material migrates to opposite poles in the cell (drawn apart by the mitotic spindle) - Two new nuclei are formed with their own nuclear envelopes, but still within the original cell - **Cytokinesis** - Cytoplasmic components are separated by an actin ring - The two daughter cells are pinched apart at the cleavage furrow # CELL CYCLE CHECKPOINTS - Diagram: https://www.ncbi.nlm.nih.gov/ - G₁ Checkpoint - G₂ Checkpoint - M Checkpoint - Formation of 2 daughter cells - Cell growth - DNA synthesis ## Cell passage through the phases of cell division is controlled by checkpoints: - Ensures processes are completed before moving to next phase - Prevents a compromised cell from multiplying ## Three major checkpoints (if they fail, you're in trouble): - Near the end of G₁ "G₁/S" checkpoint ("restriction" point) - A cell that does not meet all the requirements, will not be released from G₁ to progress to the S-phase - At the G₂-M transition - Ensures that all chromosomes have been replicated & that the replicated DNA is not damaged - During Metaphase "spindle" checkpoint - Determines whether all sister chromatids are correctly attached to the spindle # EUKARYOTIC CYCLE - Diagram: https://www.ncbi.nlm.nih.gov/ - G₁ - G₂ - G₀ - Cells not actively dividing - M # MITOSIS GONE WRONG - Most errors during eukaryotic cell division occur during · S-phase (chromosome duplication) - · Metaphase (chromosome distribution)- - **Errors during S-phase mostly polymerase errors** - Mistakes in duplication of chromosomes (DNA replication) - Mismatch of nucleic acids during replication error on one of the new DNA strands - **Division results in one normal cell and one mutant cell** ## Examples: - Tumour suppressor genes (e.g. p53) - normally send "stop" signals, preventing the cell from dividing, or induces apoptosis of damaged cells (if mutated loss of control cells keep dividing -> cancer) - Proto-oncogenes control "go" signals for cell division & progress through the cell cycle (if mutated loss of control - possible cancer) # M-PHASE & CYTOKINESIS - **Prophase** - Chromosomes condense and become visible - Spindle fibers emerge from the centrosomes. - Nuclear envelope breaks down. - Centrosomes move toward opposite poles. - **Prometaphase** - Chromosomes continue to condense. - Kinetochores appear at the centromeres. - Mitotic spindle microtubules attach to kinetochores. - **Metaphase** - Chromosomes are lined up at the metaphase plate. - Each sister chromatid is attached to a spindle fiber originating from opposite poles. - **Anaphase** - Centromeres split in two. - Sister chromatids (now called chromosomes) are pulled toward opposite poles. - Certain spindle fibers begin to elongate the cell. - **Telophase** - Chromosomes arrive at opposite poles and begin to decondense. - Nuclear envelope material surrounds each set of chromosomes. - The mitotic spindle breaks down. - Spindle fibers continue to push poles apart. - **Cytokinesis** - Animal cells: a cleavage furrow separates the daughter cells. - Plant cells: a cell plate, the precursor to a new cell wall, separates the daughter cells. - Diagram: - Credit "diagrams", modification of work by Mariana Ruiz Villareal: credit "mitosis micrographs": modification of work by Roy van Heesbeen; credit "cytokinesis micrograph"; modification of work by the Wadsworth Center, NY State Department of Health; scale-bar data from Matt Russell # MITOSIS GONE WRONG (cont.) - Errors during metaphase - Mistakes in distribution of chromosomes & genes to the metaphase plate (If duplicate chromosomes do not pair properly at the metaphase plate * will not move properly to each pole during anaphase) - Division results in two mutant cells ## Examples - Cells with extra or missing chromosomes - aneuploidy - If a break occurs during mitotic movement = chromosome damage - If a portion is lost = "deletion" - If the lost portion is reattached upside down = "inversion" - If the lost portion attaches to a different chromosome = "translocation" - can result in syndromes (e.g. Down Syndrome), lymphomas, leukaemias - E.g. Philadelphia chromosome (part of chromosome 9 transferred to chromosome 22) can cause chronic myeloid leukemia (CML) # EUKARYOTIC CYCLE - Diagram: https://www.ncbi.nlm.nih.gov/ - G₁ - G₂ - G₀ - Cells not actively dividing - M # MITOSIS GONE WRONG (cont.) - If errors during cell cycle result in uncontrolled cell growth = cancer - Tumour = cluster of (cancer) cells going through uncontrolled mitosis - If cancerous cells spread to other locations = metastases ## General traits of cancerous cells - Uncontrolled mitosis (during M-phase) - Faster growth than normal cells (during G₁ & G₂ of Interphase) - Different physical structure from normal cells - often with parts that allow them to grip & grab onto other cells & tissues ## How do you treat cancer? - two main approaches - Fix the problem (e.g. bone marrow transplant - donate correct cells) - Create problems for the cancerous cells (e.g. interfere with mitosis) - Treatment approaches & regimes as per subsequent lecture/s # TREATMENT EXAMPLES - Diagram: 2008 Renee Cannon - Dividing cancer cell - Antimetabolites - Topoisomerase inhibitors - Taxanes - Vinca alkaloids - Alkylating agents # QUESTIONS - Diagram: - Cell growth - DNA synthesis - G₁ Checkpoint - M checkpoint - Formation of 2 daughter cells