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Key Events in the Cell Cycle

Key Events in the Cell Cycle. Corrected Slide from Lecture 17- New Title. The Spindle Assembly Checkpoint Blocks Activation of the Anaphase Promoting Complex (APC ). Check for: Proper Chromosome Attachment to Spindle Phosphorylation of APC- now Activated Sister Chromatids Can Separate

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Key Events in the Cell Cycle

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  1. Key Events in the Cell Cycle

  2. Corrected Slide from Lecture 17- New Title The Spindle Assembly Checkpoint Blocks Activation of the Anaphase Promoting Complex (APC) Check for: Proper Chromosome Attachment to Spindle Phosphorylation of APC- now Activated Sister Chromatids Can Separate If Chromosomes not Properly Attached Metaphase Arrest Will not Separate

  3. Cell DivisionLecture 18 We will revisit and complete Apoptosis Lecture on Monday

  4. Cell Cycle Overview

  5. Preparation for the Onset of M-phase Duplication of Chromosomes • Member of pair referred to as Sister Chromatid • Held together by Proteins Complexes called Cohesions Duplication of Centrosomes • Centriole Pair and other Components Duplicated • Remain Together as a Single Complex in Nucleus

  6. G2 PROMETAPHASE PROPHASE Centrosomes(with centriole pairs) Aster Fragmentsof nuclearenvelope Kinetochore Chromatin (duplicated) Centromere Nonkinetochoremicrotubules Nuclearenvelope Plasma membrane Nucleolus Kinetochore microtubule M phase in Animal Cells Depends upon Chromosome and Centrosome Duplication in the Preceding Interphase MT IF

  7. DNA Replication Centromeres Replicated Chromosomes Are Composed of Two Sister Chromatids Held Together by Cohesion Protein Complexes Sister Chromatids

  8. M-phase Requires Formation of a New Apparatus Called the Mitotic Spindle A Symmetrical, Bipolar Structure composed of Microtubules- with associated Motors and Other Proteins Each pole has a Centrosome Functions in M-phase: • Responsible for Separating the Replicated Chromosomes into Daughter Nuclei during Division of the Nucleus • Directs the Process of Dividing the Cytoplasm

  9. Centrosome Duplication is Required for the Formation of a Bipolar Mitotic Spindle

  10. M-CDK Activity is Required for Mitosis • Key Ways to Regulate CDK Complex Activity: • Proteolysis of Cyclin Subunit • Phosphorylation/ Dephosphorylation • Binding by Inhibitors • Subcellular Localization

  11. Mitosis Requires Active M-CDK During G2- Cyclin Levels are Increasing Form M-CDK Complexes But Held Inactive due to Inhibitory Phosphate

  12. Active M-CDK Indirectly Activates More M-CDK Leads to Sudden Explosive Increase in Active M-CDK Levels

  13. M–CDK Activity is Required for Triggering the Mitotic Machinery 1) Phosphorylation and Activation of Various Kinases 2) Direct Phosphorylation of Targets • Chromosome Condensation • Assembly of Mitotic Spindle • Nuclear Envelope Breakdown

  14. Stages of Mitosis:Prophase • Individual Replicated Chromosomes Condense • Nucleoli Disperse (in Animal Cells) • Two Centrosomes Separate From Each Other • Assembly of the Mitotic Spindle Outside of the Nucleus

  15. Chromosome Condensation During Prophase:M-CDK Phosphorylates Condensin Proteins Cohesions Keep Sister Chromatids Together Condensins bind DNA Phosphorylated by M-CDK Results in Chromosome Condensation

  16. G2 to Prophase Transition PROMETAPHASE G2 PROPHASE Centrosomes(with centriole pairs) Aster Chromatin(duplicated) Early mitoticspindle Kinetochore Centromere Nonkinetochoremicrotubules Chromosome, consistingof two sister chromatids Plasmamembrane Nucleolus Kinetochore microtubule Nuclearenvelope

  17. Prometaphase Marked by: 1) The Breakdown of Nuclear Envelope 2) Kinetochores Assembled on Chromosomes can now be attached to Spindle Microtubules 3) Chromosomes Attach to Mitotic Spindle Begin to move around

  18. Nuclear Envelope Breakdown Marks Transition into Prometaphase by M-CDK

  19. A Kinetochore Assembles on the Centromere Region of Each Sister Chromatid One Kinetochore Per Chromatid Sister Chromatids

  20. G2 OF INTERPHASE PROMETAPHASE PROPHASE Aster Centrosomes(with centriole pairs) Fragmentsof nuclearenvelope Kinetochore Early mitoticspindle Chromatin(duplicated) Nucleolus Nuclearenvelope Plasmamembrane Chromosome, consistingof two sister chromatids Kinetochore microtubules Prophase to Prometaphase Transition Interpolar Microtubules Now MT Have Access To Chromosomes!

  21. Classification of Spindle Microtubules Kinetochore Microtubules- Attach to Kinetochores Polar Microtubules- Interact with Microtubules from Opposite Pole of the Cell Astral Microtubules- Nucleate from Centrosome Some Interact with Motor Proteins Associated with at Cell Cortex

  22. Organization of the Mitotic Spindle

  23. METAPHASE ANAPHASE TELOPHASE AND CYTOKINESIS Metaphaseplate Cleavagefurrow Nucleolusforming Bipolar Spindle Daughter chromosomes Nuclear envelopereforming Centrosome atone spindle pole Metaphase Maximal Chromosome Condensation Aligned at Metaphase Plate -Not actually still- jerky motions due to constant tension Forces Acting on Chromosomes to Align them At Metaphase Plate

  24. Anaphase Abrupt Separation of Sister Chromatids Movement to Chromosomes to Opposite Pole Cell Elongates For Anaphase to Occur: 1) Activation of the Anaphase Promoting Complex (APC) Mediated Indirectly through M-CDK 2) Must Pass : SPINDLE ATTACHMENT CHECKPOINT All Chromosomes are properly attached to the spindle before Sister Chromatid Separation Occurs

  25. Activation of the Anaphase Promoting Complex (APC), a Highly Regulated Ubiquitin Ligase APC Functions to Bring About: • Cleavage of Cohesion Complex to Separate Sister Chromatids (through proteolytic degradation of inhibitory protein) • Proteolytic Cleavage and Inactivation of M-phase Cyclin thereby inactivating M-CDK

  26. Chromatin changes Transcription RNA processing Proteasome and ubiquitin to be recycled E3 Translation mRNA degradation Proteasome Protein processing and degradation Degradation Signal E3 Protein to be degraded Ubiquinated protein Protein fragments (peptides) Protein entering a proteasome E2 E2 Proteasome Degradation (APC) Key Targets: Securin And Cyclin of M-CDK

  27. The Mechanism of Separation of Sister Chromatids Requires APC Activity Securin Separase Spindle Attachment Checkpoint: If A Kinetochore is Not Attached to The Spindle It Is Sensed The APC is Kept Inactive T APC-Anaphase Promoting Complex

  28. METAPHASE ANAPHASE TELOPHASE AND CYTOKINESIS Metaphaseplate Cleavagefurrow Nucleolusforming Daughter chromosomes Nuclear envelopereforming Centrosome atone spindle pole Chromosome Separation During ANAPHASE Anaphase A- Sister Chromatids are Pulled to Opposite Poles Centromeres First Toward the Spindle Poles as Kinetochore MT Depolymerize Anaphase B- The Spindle Poles Move Away from Each Other as Polar MT Lengthen Anaphase A and B May Occur Simultaneously or Shortly After One Another Movements Rely on Motor Proteins that Associate with the Various MT

  29. Movement Involved in Daughter Chromosome Separation During Anaphase A Anaphase A Movement Plus End of Kinetochore Microtubules Dissassembles Minus End Directed Motor (Dynein) Proteins Pull Toward Spindle Pole Pac Man Mechanism MT Depolymerize Dynein Walks Toward Minus End (-) Taxol Inhibits Grows to 2X the Metaphase Length

  30. Movement Involved in Daughter Chromosome Separation During Anaphase B Polar MT Assembly Occurs at Plus End Plus End Directed Motor Proteins of Antiparallel Polar MT Slide Filaments 2.Astral MT Motor Proteins- Cytoplasmic Dynein Attach to Cell Cortex Moving toward Centrosome -Exert Outward pull on the spindle- help separate spindle poles 1. 2. Taxol Inhibits

  31. Cytokinesis Divides the Cytoplasm Usually starts in late Anaphase and continues through Telophase (once sister chromatids are separated) Occurs by a Process called Cleavage in Animal Cells Requires Formation of a Contractile Ring Contractile Ring: A Dynamic Assembly of Actin, Bipolar Myosin II Filaments, and many structural and regulatory proteins Forms Under Surface of Plasma Membrane and Contracts to Pinch Two Daughter Cells Apart Cytokinesis Cannot Occur Until: 1) M-CDK is Inactivated- M-cyclin Targeted by APC for destruction by proteasome 2) Sister Chromatids have migrated to opposite poles of the cell – Remaining MT form Midbody - determines where Contractile Ring Formation will occur

  32. Cleavage Requires The Contractile Ring • Remaining Polar MT • form Midbody • Determines where • Contractile Ring • Formation will occur

  33. Cleavage Furrow Formation in Animal Cells • 1)Slight Indentation or Puckering on Cell Surface • 2) Rapidly Deepens to Form Cleavage Furrow • 3) Continues Until Opposite Surfaces Make Contact • and Cell is Split in Two.

  34. Telophase 1)Sister Chromatids have arrived at poles of the spindle 2) Now M-cyclin Degraded by APC Reversal of M-CDK Effects Including: -Nuclear Envelope Reforms around two groups of daughter chromosomes to form Two Interphase Nuclei -Chromosomes Decondense -Disassembly of Mitotic Spindle

  35. Nuclear Envelope and Portions of Endomembrane System Reform During Telophase

  36. METAPHASE ANAPHASE TELOPHASE AND CYTOKINESIS Metaphaseplate Cleavagefurrow Nucleolusforming Daughter chromosomes Nuclear envelopereforming Centrosome atone spindle pole Completion of Mitotic Phase of Cell Cycle

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