Cell Cycle and Radiosensitivity

1. Cell Cycle and Radiosensitivity Wenqing Sun Sept. 27, 2000

2. Agenda • Definition of cell cycle • Radiosensitivity at different cell phase • Cell cycle checkpoint • Other aspects of radiation biology and cell cycle

3. Definition of Cell Cycle • Cell Cycle is ordered process by which one cell grows and divides into two daughter cells.

4. Phases of Cell Cycle • Mitosis - M phase • One cell divides into two identical cells. • Typically lasts for 30 minutes.

5. Phases of Cell Cycle - continued • Interphase • S phase • Lasts 6 hours. • DNA synthesis is restricted to this phase. • G1 phase • Duration varies dramatically for different cell lines. • G2 phase • Lasts 3 hours.

6. Cell populations and cell cycle phases

7. Cell growth and DNA content during the cell cycle

8. Comparison of Cell Cycle - Hamster and Hela

9. Radiosensitivity at different cell phase

10. Time-survival fraction for Hamster cell

11. Time-survival fraction for HeLa cell

12. Correlation between variation of radiosensitivity and age • Cell are most sensitive at or close to mitosis • Resistance is usually greatest in the latter part of S phase • If G1has an appreciable length, a resistant period is evident early in G1 phase, followed by a sensitive period toward the end of G1 phase • G2phase is usually sensitive, perhaps as sensitive as M phase

13. Cell Cycle Checkpoint • Definition of cell cycle checkpoint • Events that can initiate the arrest of cell cycle at checkpoints • Arrests of each phase

14. Definition of Checkpoint • Cell cycle is a highly ordered process:the initiation of later event depends on the completion of earlier events. • The control mechanisms that enforce this ordered dependency are called cell cycle checkpoint.

15. Events can initiate arrest • Nutrient deprivation • Temperature changes • Nucleotide depletion • Damage to the DNA

16. DNA-damage-responded checkpoint

17. Some conception • Oncogenes • Tumor suppressor genes • Cyclin is a family of proteins required for the activity of some kind of kinases. • Cyclin-dependent kinases: a group of kinases that can regulate cell cycle progress

18. G1 phase arrest • Avoid DNA replication • Dependent on the function status of p53

19. G1 arrest and p53 pathway • Irradiation--->DNA damage---> increasing level of p53 protein---> activation of p21WAF1/CIP1 gene---> inhibition the activity of cyclin/CDK---> G1 arrest

20. S phase arrest • After relatively high dose irradiation • Prevent DNA replication errors • Inhibiting the initiation of replicon or inhibiting the elongation of replicon • The mechanism is not clear

21. G2 phase arrest • Very important checkpoint • Prevent the cells with damaged DNA to progress into mitosis

22. Mechanism of G2 arrest • The control gene in yeast • cyclin B1 and p34cdc2 • ras oncogene

23. Methods to control checkpoint • Gene therapy: success and difficulty • drugs

24. Other aspects of cell cycle • LET • Hyperthermia • Cell cycle redistribution

25. LET and cell cycle

26. LET-Respond Cell Cycle Sensitivity

27. Hyperthermia and cell cycle

28. Cell Age-respond Sensitivity to Hyperthermia

29. Mechanism of hyperthermia • Thermersensitivity and cell cycle • Biological effect of hyperthermia • hyperthermia and oxygen • Block the repair of DNA damage

30. Cell Cycle Redistribution

31. The overall effect of a dose of radiation • kill cells in a sensitive phase of the cell cycle • Sensitize a cycling population to a later dose of radiation. • Leave majority of cells in a resistant cell cycle phase. • All of the above

32. Artificial synchronization • Redistribution(re-assortment)