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Feedback Control Between S-phase and Mitosis

Feedback Control Between S-phase and Mitosis. Feedback control ensures dependency of cell cycle events. DNA Damage Checkpoints. Sensors: (i.e. Rad9). Transducers:. Targets:. :Targets. From Susan Forsburg, Salk Institute. http://pingu.salk.edu/~forsburg/cclecture.html.

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Feedback Control Between S-phase and Mitosis

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  1. Feedback Control Between S-phase and Mitosis Feedback control ensures dependency of cell cycle events

  2. DNA Damage Checkpoints Sensors: (i.e. Rad9) Transducers: Targets: :Targets From Susan Forsburg, Salk Institute http://pingu.salk.edu/~forsburg/cclecture.html

  3. Chromosome Movements During Mitosis From Rieder and Salmon (1998) Trends Cell Biol. 8:310

  4. What if There Were No Checkpoint? Lodish et al. Figure 13-33

  5. The Mitotic Spindle Assembly Checkpoint Ensures the Order of Mitotic Events What has to Happen for Proper Chromosome Segregation? - Sister Chromatid Cohesion established in S-phase - Chromosome condensation in G2 - Mitotic Spindle Assembly in Mitosis - Chromosome alignment in Mitosis - Metaphase/Anaphase transition (M/A) -securin degradation leads to cohesion destruction Mitotic checkpoint has to be upstream of M/A - Once you start destroying cohesion there’s no going back

  6. The Mitotic Spindle Assembly Checkpoint aka Kinetochore Checkpoint Mitotic Checkpoint Metaphase Checkpoint Spindle Checkpoint… Mitotic Checkpoint Inhibits Cohesion Destruction -via inhibition of APCCdc20 Mitotic Checkpoint Also Inhibits Mitotic Exit -via inhibition of APCCdh1

  7. The Metaphase to Anaphase (M/A) Transition From Zhou et al. (2002) J. Cell Sci. 115:3547

  8. How do We Know There’s a Checkpoint? Prometaphase Metaphase Adapted From Shimoda and Solomon (2002) Cell 109:9

  9. Variable 20 min. How do We Know There’s a Checkpoint? Prometaphase Metaphase Regardless of the length of Prometaphase, Metaphse lasts 20 minutes… Adapted From Shimoda and Solomon (2002) Cell 109:9

  10. Cohesion is Established in S-phase Cdc6 MCM Proteins ORC ORC ORC preRC Origin Assembly / Activation Actvie Cohesin Replication Factors Cdc28 Cdc28 ORC ORC ORC Cdc7 Elongating Repl. Fork Origin Firing Origin Inactivation From Susan Forsburg, Salk Institute http://pingu.salk.edu/~forsburg/cclecture.html

  11. Cohesion is Established in S-phase Pds5 Scc3 Scc1 Smc1 Smc3 Cohesin Condensin From Uhlman (2001) Cur. Op. Cell Biol. 13:754

  12. Cohesion is Established in S-phase Cohesin Condensin Chromosome Cohesion Chromosome Compaction Scissile Subunit (Scc1) Cleaved at M/A From Uhlman (2001) Cur. Op. Cell Biol. 13:754

  13. Condensin is Required for Chromosome Compaction Cohesin is Required for Chromosome Compaction

  14. Condensin is Required for Chromosome Compaction Cohesin is Required for Chromosome Compaction CohesinlinksCondensin from adjacent sister chromatids

  15. From Susan Forsburg, Salk Institute http://pingu.salk.edu/~forsburg/cclecture.html

  16. The Metaphase to Anaphase (M/A) Transition From Zhou et al. (2002) J. Cell Sci. 115:3547

  17. Evidence for the Existence of a Checkpoint Needle 20 min. Micromanipulation of Chromosomes in Grasshopper Spermatocytes Adapted From Nicklas (1997) Science 275:632

  18. Micromanipulation of Chromosomes in Grasshopper Spermatocytes From Nicklas (1997) Science 275:632

  19. Variable 20 min. Kinetochores Generate the Checkpoint Signal Adapted From Shimoda and Solomon (2002) Cell 109:9

  20. Variable 20 min. Kinetochores Generate the Checkpoint Signal 20 min Laser Ablate Kinetochore from last Mono-oriented Chromosome Adapted From Shimoda and Solomon (2002) Cell 109:9

  21. From Rieder et al. (1995) J. Cell Biol. 130:941

  22. Laser Anaphase From Rieder et al. (1995) J. Cell Biol. 130:941

  23. Unattached Kinetochores Cause a Checkpoint Delay From Musacchio and Hardwick (2002) Nature Reviews 2:731

  24. Both Attachment and Tension are Monitored 3F3 Epitope Phosphorylation of unknown proteins -dims upon attachment -disappears upon tension From Rieder and Salmon (1998) Trends Cell Biol. 8:310

  25. Both Attachment and Tension are Monitored Mono-oriented Grasshopper Spermatocyte Chromosomes Relaxed Tension Applied 3F3 Epitope Present in the absence of tension 3F3 Epitope Disappears when tension applied Adapted From Nicklas (1997) Science 275:632

  26. One More Yeast Screen: MADs and BUBs Search for Genes Responsible for Feedback Control of Mitosis Hoyt: Budding Uninhibited by Benomyl Bub1, Bub2, Bub3 Li: Mitotic Arrest Deficient Mad1, Mad2, Mad3

  27. Spindle Assembly Checkpoint Components

  28. APC is the Target of the Mitotic Checkpoint The Metaphase to Anaphase (M/A) Transition From Zhou et al. (2002) J. Cell Sci. 115:3547

  29. Potential Checkpoint Targets:

  30. APC is the Target of the Mitotic Checkpoint From Zhou et al. (2002) J. Cell Sci. 115:3547

  31. APC is the Target of the Mitotic Checkpoint Cdc2/Cyclin B Mad2 Mad3/BubR1 Bub2 Cdc2/Cyclin B Adapted from Peters (2002) Mol. Cell 9:931

  32. Spindle Assembly Checkpoint Pathways Securin Separase Adapted From Susan Forsburg, Salk Institute http://pingu.salk.edu/~forsburg/cclecture.html

  33. Mitotic Exit is a Spindle Checkpoint Target Bub2 active: NO Cdc14 Release Mitotic Exit Network (MEN) Bub2 inactive: Cdc14 Released From Susan Forsburg, Salk Institute http://pingu.salk.edu/~forsburg/cclecture.html

  34. Cdc14 Cdc2/Cyclin B Cdc2/Cyclin B Cdc14 Sequestered in Nucleolus Cdc14 Released Bub2 Prevents Cdc14 Release/Cdh1 Activation Bub2 Bub2

  35. APC is the Target of the Mitotic Checkpoint Cdc2/Cyclin B Mad2 Mad3/BubR1 Bub2 Cdc2/Cyclin B Adapted from Peters (2002) Mol. Cell 9:931

  36. Spindle Assembly Checkpoint Pathways Securin Separase From Susan Forsburg, Salk Institute http://pingu.salk.edu/~forsburg/cclecture.html

  37. Checkpoint is Mediated by Rearrangement of Mad2 Complexes Mad2 Inhibits APCCdc20 From Millband et al. (2002) Trends Cell Biol. 12:205

  38. Mad2 Cycles Through Kinetochore and Inhibits Cdc20 Shah and Cleveland (2000) Cell 103:997

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