AH Biology: Unit 1 Control of the Cell Cycle

1. AH Biology: Unit 1 Control of the Cell Cycle

2. The cell cycle: summary G1 Cytokinesis Interphase M Mitosis S G2

3. The cell cycle: summary G1 Cytokinesis Telophase Interphase Anaphase M Metaphase Prophase S Mitosis G2

4. Why does the progress of a cell through the cell cycle need to be monitored and regulated? • What features should an effective cell cycle control system possess?

5. The cell cycle control system can be studied using model organisms • Yeast: Identification of mutations that arrest the cell cycle at specific points. Affected genes are known as cell-division-cycle (cdc) genes.

6. The cell cycle contains control points G1 G1 checkpoint (entry to S phase) M checkpoint (exit from M phase) I M S G2 checkpoint (entry to M phase) G2

7. The cell cycle contains control points G1 G1 checkpoint (initiation of DNA replication) M checkpoint (initiation of anaphase) I M S G2 checkpoint (assembly of spindle fibres) G2

8. The control points are checkpoints for the cell cycle control system If events have not been completed the control system receives signals and arrests the cell cycle. G1 checkpoint: Has the cell reached a sufficient size? Are environmental conditions favourable? M checkpoint: Are all chromsomes attached to spindle fibres? G1 I M G2 checkpoint: Has all nuclear DNA been replicated? S G2

9. The G1 checkpoint • Timing: Towards the end of G1 phase. • Controls: Entry to S phase (triggers the initiation of DNA replication). • Assesses: Cell size and environmental conditions. • Purpose: Ensures that sufficient cell growth has occurred and environmental conditions are favourable for proliferation.

10. What could happen to a yeast cell whose G1 checkpoint mechanism has been inactivated?

11. With nutritional cell cycle control Cell size Without nutritional cell cycle control Time Nutrient supply reduced

12. In multicellular organisms the G1 checkpoint operates through intracellular and extracellular signals Fibroblast grown in culture with adequate nutrient supply and serum Fibroblast grown in culture with adequate nutrient supply and plasma Cell progresses through cycle and proliferates Cell cycle is arrested

13. Serum contains a protein that can bind to cells and stimulate them to progress through the cell cycle. Extracellular signal molecules with this function are called mitogens.

14. The most important decision • Cells may either proliferate or leave the cell cycle. • In the absence of mitogens cells enter a non-dividing state called the G0 phase. • Cells can become terminally differentiated and remain in G0 permanently or re-enter the cell cycle when they receive appropriate signals.

15. G0 Reversibility depends on cell type G1 Cytokinesis Interphase M Mitosis S G2

16. Some types of cell can proliferate continuously • Stem cells • Tumour cells

17. Most liver cells exist in a reversible G0 phase G0 G0 Cell proliferation is stimulated by damage to liver Normal hepatocyte: mitogenic signal absent G1 G1 I I M M S S G2 G2

18. Red blood cells, neurons and skeletal muscle cells exist in a terminally differentiated G0 state

19. The G2 checkpoint • Timing: End of G2 phase. • Controls: Entry to M phase (triggers assembly of mitotic structures). • Assesses: Completion of DNA replication. • Purpose: Ensures that all DNA is replicated so that daughter cells can each receive a complete copy of the genome and function correctly.

20. The M checkpoint • Timing: During metaphase. • Controls: Exit from M phase (triggers anaphase and cytokinesis). • Assesses: Attachment of all chromosomes to spindle fibres. • Purpose: Ensures that each daughter cell receives the same chromosome complement as its parent when anaphase occurs.

21. The M checkpoint All chromosomes attached to spindle fibres One chromosome is not attached to spindle fibres Cell cycle progresses: cell enters anaphase Cell cycle arrested until all chromosomes are properly attached

23. Checkpoints operate through negative intracellular signals • The presence of unattached chromosomes generates signals that stop the cell from progressing to anaphase.

24. The molecular mechanisms of cell cycle control

25. The cell cycle is controlled by the activity of cyclin-dependent kinases (Cdks) Cdk inactive G1 Cdk active M S Cdk inactive Cdk active G2

26. The cell cycle control system can be studied using model organisms • Spisula: a mollusc used in the study of protein synthesis (eg of cyclins) in embryonic cells.

27. A time course of intracellular cyclin protein Relative level of cyclin protein Mitosis Mitosis Mitosis Time

28. The activity of Cdks is regulated by cyclins Cyclin binding Cdk with protein kinase activity (cyclin–cdk complex) Inactive Cdk

29. Different cyclins bind to Cdks at different phases of the cell cycle • The binding of G1-cyclins allows a cell to pass through the G1 checkpoint. • The binding of S-cyclins allows a cell to initiate DNA replication in the S phase. • The binding of M-cyclins promotes the events of mitosis.

30. The activation of cyclin-Cdk complexes triggers cell cycle events G1-Cdk G1 M M-Cdk DNA replication triggered S-Cdk S Mitosis triggered A certain level of phosphorylation of target proteins results in the cell progressing to the next stage of the cycle. G2

31. Active retinoblastoma protein (Rb) inhibits cell cycle progression G1 S

32. Retinoblastoma is targeted by G1-Cdk Synthesis of S-cyclins Active G1-Cdk Active Rb Inactive Rb Active S-Cdk P P DNA replication What would be the consequence of a mutation to the gene that codes for the Rb protein?

33. The cell cycle has checkpoints for DNA damage Mutagen In which part(s) of the cell cycle would you expect these checkpoints to occur?What should a cell with damaged DNA do?

34. DNA damage prior results in the activation of the protein p53 1. Damaged DNA 2. Protein kinase activity triggered P Stable p53 Unstable p53

35. Active p53 can promote the transcription of genes that induce cell cycle arrest P Regulatory DNA Expression of p21 gene p21 protein Cyclin–Cdk complex inactivated Cell arrested in G1

36. Active p53 can affect a cell in different ways Promotes transcription of genes that induce apoptosis Stimulates DNA repair P Promotes transcription of genes that induce cell cycle arrest What would be the functional consequences of an inability to activate p53?

37. Ataxia telangiectasia: a genetic disease associated with an inability to activate p53 What could cause the development of telangiectases (small clusters of enlarged blood vessels)?

38. Cell cycle review Interactive cell cycle animation. Control of cell cycle game on the Nobel Prize website (simulation). Animation of the action of the Rb and p53 proteins.