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BIOL 200 (Section 921) Lecture # 12; July 5, 2006

BIOL 200 (Section 921) Lecture # 12; July 5, 2006. Unit 9: Cell Cycle, Cell division Readings: I. Cell cycle: ECB 2nd ed., Chapter 19, pp. 637-40. Overview of the cell cycle; Chapter 18, pp. 611-25. Good questions: 18-2, 18-3, 18-4; 18-7a, d, e; 18-10; 18-15; 18-16.

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BIOL 200 (Section 921) Lecture # 12; July 5, 2006

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  1. BIOL 200 (Section 921)Lecture # 12; July 5, 2006 Unit 9: Cell Cycle, Cell division Readings: • I. Cell cycle: ECB 2nd ed., Chapter 19, pp. 637-40. Overview of the cell cycle; Chapter 18, pp. 611-25. Good questions: 18-2, 18-3, 18-4; 18-7a, d, e; 18-10; 18-15; 18-16. ECB 1st ed., Chapter 17, pp. 547-550. [Skim pp. 551-560] Overview of the cell cycle; Chapter 18, pp. 571-581. • II. DNA replication: ECB 2nd ed.,Chapter 6, pp. 196-208 DNA Replication; Questions # 6-9, 6-10, 6-11 (very good). ECB 1st ed.,Chapter 6, pp. 189-197 DNA Replication; Questions # 6-14, 6-15, 6-16 (very good) • III. Chromosomes and Mitosis: ECB 2nd ed.,Chapter 19 pp 639-55 for Mitosis. Good questions: 19-3, 19-4; 19-5; 19-8; 19-10; 19-12; 19-14. ECB 1st ed.,Chapter 8, p 249-50 Telomeres: Specialized structures ensure that chromosomes replicate efficiently; Chapter 17 pp 551-562 for Mitosis

  2. Learning objectives I. Introduction and Overview of Cell Cycle; Regulation of cell cycle by CDK-cyclin • Understand overall organization of the cell cycle and its relation to cell division (mitosis and cytokinesis): • Be able to list cell cycle stages in order and indicate the location of the two major cell cycle control points. • Give examples of discrete and continuous cell cycle processes. • Understand the checkpoint concept and how this allows Integration of continuous and discrete cell cycle processes • Understand the role of CDK-cyclin in regulation of cell cycle processes. • Be able to explain how the CDK complex is regulated by protein phosphorylation, and by proteolysis. II. DNA Replication • Explain what is meant by semi-conservative replication of DNA. • Explain how DNA replication occurs in eukaryotes through the independent operation of many replicons. • Describe the roles of the following in DNA replication: Helicase, DNA polymerase, primer, Okazaki fragments, ligase. • Explain the terms lagging and leading strand and the significance of these terms for DNA replication. • Understand the relation between chromatids and chromosomes in both pre- and post-replication stages • Explain and understand replicon and replication fork. III. Chromosomes and Mitosis • Understand why telomeres are important and how telomere extension occurs • List the stages of mitosis in order and explain what is happening to the cytoskeleton, the mitotic spindle, the nuclear envelope and the chromosomes during this process. • Explain how chromosomes are moved to the poles at mitosis. • What are kinetochores and what are they good for.

  3. Cell cycle • Cells arise from pre-existing cells • The reproduction of cells takes place in an orderly fashion and is genetically regulated • Cells reproduce by a process called the cell cycle which show (i) cell growth and chromosome replication, (ii) chromosome segregation and (iii) cell division • Each cell type has its own timing and built-in memory • For example, cell cycle time varies from about 0.5 hours in early frog embryo cells to about 1 year in human liver cells

  4. Four phases of the cell cycle [Fig. 18-2] • M phase includes nuclear division and cytokinesis • G1 – the interval between M and S phases • S phase – replication • G2 – the interval between S phase and mitosis

  5. A central control system (like a washing machine) triggers the major processes of the cell cycle [Fig. 18-3] • Like a clothes-washing machine, there is a feedback at each stage • The next stage can not begin until the previous one has ended • This is a system of checkpoints

  6. Two major checkpoints in the cell cycle • There is a checkpoint in G1 for cell size. If the cell has not grown sufficiently, it will be held in G1 until that happens • Similarly, there is a checkpoint in G2 that ensures replication is complete before mitosis begins • Checkpoints also take into account signals from other cells and environment. ‘COMMITMENT TO DIVN.’ ‘START’

  7. Xenopus egg, does not divide unless activated [Fig. 18-8]

  8. microinjection of cytoplasm extract into egg activates mitosis [Fig. 18-9] Inject cytoplasm from m phase cell Inject cytoplasm From interphase cell Promotes mitosis No mitosis, stays in interphase CONCLUSION: Some kind of cytoplasmic factor promotes cell division – called m phase promoting factor (MPF)

  9. Cyclin-CDK complex [Fig. 18-5] Cyclin-amount varies during cell cycle Cyclin-dependent kinase (Cdk)

  10. The major Cyclins and Cdks [Table 18-2] -------------------------------------------------------- Cyclin-Cdk Cyclin Cdk partner Complex --------------- ----------- --------------- G1-Cdk cyclin D Cdk4, Cdk6 G1/S-Cdk cyclin E Cdk2 S-Cdk cyclin A Cdk2 M-Cdk cyclin B Cdk1 --------------------------------------------------------

  11. Changes in [M-cyclin] and M-Cdk activity during the cell cycle [Fig. 18-6]

  12. Factors affecting the activity of Cdks • Cyclin degradation by ubiquitination • Phosphorylation and dephosphorylation • Positive feedback • Cdk inhibitor proteins

  13. Cyclin degradation by ubiquitination inhibits the activity of Cdks [Fig. 18-7] 18_07_cyclin_degradat.jpg

  14. Phosphorylation and Dephosphorylation • Cell cycle control is regulated by phosphorylation and dephosphorylation • Protein kinases and phosphatases form a switch • Protein kinases that control cell cycle are present throughout the cell cycle. Their activity rises and falls. • A second set of proteins CYCLINS have no enzyme activity themselves. They bind to kinases and activate them. • The kinases of the cell cycle control system are known as cyclin-depedent protein kinases or Cdks.

  15. Protein phosphorylation [Fig. 4-41] kinase adds Phosphatase removes phosphate group

  16. Protein phosphorylation acts as a switch to modify protein activity [Fig. 4-41]

  17. Selective phosphorylation and dephosphorylationactivate M-Cdk [Fig. 18-11] 18_11_M_Cdk_active.jpg Thr 14, Tyr 15 Thr 161

  18. Fig. 18-12: CDK phosphorylates activating phosphatase: further activation of CDK via a positive feedback loop.

  19. Different cyclin-Cdk complexes trigger different events in cell cycle [Fig. 18-13] 18_13_Cdks_cyclins.jpg

  20. M-Cdk effects • M-Cdk contains a single protein kinase, which triggers mitosis • It phosphorylates MAPs and causes cytoskeleton to reorganize – forming the spindle • It posphorylates the nuclear lamina and causes the nuclear envelope to break down. • It phosphorylates non-histone proteins and causes chromosome condensation

  21. DNA damage arrests the Cell cycle in G1 [Fig. 18-15] 18_15_cell_cycle_G1.jpg

  22. The cell-cycle control system can arrest the cycle at various checkpoints [Fig. 18-17] 18_17_arrest_checkpt.jpg Cell below critical size Cell below critical size

  23. DNA replication Learning objectives • Explain what is meant by semi-conservative replication of DNA. • Explain how DNA replication occurs in eukaryotes through the independent operation of many replicons. • Describe the roles of the following in DNA replication: Helicase, DNA polymerase, primer, Okazaki fragments, ligase. • Explain the terms lagging and leading strand and the significance of these terms for DNA replication. • Understand the relation between chromatids and chromosomes in both pre- and post-replication stages • Explain and understand replicon and replication fork

  24. Semiconservative replication of DNA: Each daughter strand has one DNA template from parental strand [Fig. 6-3] “S” PHASE

  25. Replication initiator proteins open up a DNA double helix at its replication origin [Fig. 6-5] 06_05_replic.origin.jpg

  26. 06_09_Replic.forks.jpg Replication fork moves away in both directions

  27. 06_10_5prime_3prime.jpg DNA synthesis in the 5’→3” direction

  28. The two newly synthesized DNA strands have opposite polarity 06_11_oppositepolarity.jpg

  29. DNA replication forks are asymmetrical [Fig. 6-12] 06_12_asymmetrical.jpg

  30. DNA POLYMERASE CATALYZE BOTH DNA REPLICATION AND EDITING (PROOFREADING) [Fig. 6-14] 06_14_polymerase2.jpg

  31. On the lagging strand, DNA is synthesized in fragments [Fig. 6-16] 06_16_lagging strand.jpg

  32. 06_17_group proteins.jpg A group of proteins act together at a replication fork

  33. A protein machine in DNA replication Key Players • Leading strand DNA • Lagging strand DNA • DNA Polymerase III • Helicase • RNA Primase and RNA Primers • Okazaki Fragments • Ligase • Single-stranded DNA binding proteins

  34. Becker et al. The World of the Cell]

  35. Chromosomes and Mitosis: Learning objectives • Understand why telomeres are important and how telomere extension occurs • List the stages of mitosis in order and explain what is happening to the cytoskeleton, the mitotic spindle, the nuclear envelope and the chromosomes during this process. • Explain how chromosomes are moved to the poles at mitosis. • What are kinetochores and what are they good for.

  36. 3 DNA sequences needed to produce a eukaryotic chromosome [Fig. 5-18] 1. telomere 2. origin of replication 3. centromere

  37. Telomeres allow the completion of DNA synthesis at the ends of Chromosomes [Fig. 6-18] 06_18_telomeres.jpg Telomerase contains a Short piece of RNA which acts as a primer for DNA synthesis

  38. The cytoskeleton is involved in both mitosis and cytokinesis 19_04_mediate_M.jpg

  39. Mitosis separates sister chromatids into daughter chromosomes [Fig. 19-6]

  40. Panel 19-1: prophase

  41. Mitotic chromosome [Fig. 19-3] 2 chromatids centromere What keeps the 2 chromatids together?

  42. Cohesins hold sister chromatids together. Condensins help pack chromatin into chromosomes [Fig. 19-3] Where would you expect to find cohesins in this picture?

  43. Fig. 19-5: centrosomes duplicate to form mitotic spindle poles. centrosome duplication Mitotic spindle poles

  44. Fig. 19-7: Mitotic spindle prophase Selective stabilization of interpolar MT

  45. Panel 19-1: prometaphase Dynamic instability-MT’s shoot out of spindle poles.

  46. Fig. 17-9: Kinetochore is protein complex at centromere region of chromosome MT bind here

  47. Panel 19-1: Metaphase

  48. Fig. 19-13: Mitotic spindle at metaphase Interpolar microtubules Kinetochore microtubules

  49. Panel 19-1: Anaphase

  50. Fig. 19-17: Anaphase A-sister chromosomes separate by kinetochore MT shortening

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