This section also contains suggested readings for the course.
Required Readings
| SES # | TOPICS | READINGS |
|---|---|---|
| 1 | Introduction | |
| 2 | The cell cycle |
Pines, J., and T. Hunter. "Isolation of a Human Cyclin cDNA: Evidence for Cyclin mRNA and Protein Regulation in the Cell Cycle and for Interaction with p34cdc2." Cell 58 (1989): 833-46. Simanis, V., and P. Nurse. "The Cell Cycle Control Gene cdc2+ of Fission Yeast Encodes a Protein Kinase Potentially Regulated by Phosphorylation." Cell 45 (1986): 261-8. |
| 3 | Cell cycle control – the role of the tumor suppressor pRb in the G1/S transition |
Hartwell, L. H., J. Culotti, and B. Reid. "Genetic Control of the Cell-division Cycle in Yeast, I. Detection of Mutants." PNAS 66 (1970): 352-9. Goodrich, D. W., N. P. Wang, Y. W. Quan, E. Lee, and W. H. Lee. "The Retinoblastoma Gene Product Regulates Progression Through the G1 Phase of the Cell Cycle." Cell 67 (1991): 293-302. |
| 4 | Cdk-regulation |
Parker, L. L., and H. Piwnica-Worms. "Inactivation of the p34cdc2-Cyclin B Complex by the Human WEE1 Tyrosine Kinase." Science 257 (1992): 1955-1957. Gautier, J., M. J. Solomon, R. N. Booher, J. F. Bazan, and M. W. Kirschner. "cdc25 is a Specific Tyrosine Phosphatase that Directly Activates p34cdc2." Cell 67 (1991): 197-211. |
| 5 | Checkpoint control of the cell cycle |
Matsuoka, S., M. Huang, and S. J. Elledge. "Linkage of ATM to Cell Cycle Regulation by the Chk2 Protein Kinase." Science 282 (1998): 1893-7. Brugarolas, J., C. Chandrasekaran, J. I. Gordon, D. Beach, T. Jacks, and G. J. Hannon. "Radiation-induced Cell Cycle Arrest Compromised by p21 Deficiency." Nature 377 (1995): 552-7. |
| 6 | p53 regulation |
Hirao, A., Y. Y. Kong, S. Matsuoka, A. Wakeham, J. Ruland, H. Yoshida, D. Liu, S. J. Elledge, and T. W. Mak. "DNA Damage-induced Activation of p53 by the Checkpoint Kinase Chk2." Science 287 (2000): 1824-7. Honda R., and H. Yasuda. "Association of p19ARF with Mdm2 Inhibits Ubiquitin Ligase Activity of Mdm2 for Tumor Suppressor p53." The EMBO Journal (1999) 18, 22-27. |
| 7 | The DNA damage checkpoint differs depending on cell cycle stage |
Jazayeri, A., J. Falck, C. Lukas, J. Bartek, G. C. Smith, J. Lukas, and S. P. Jackson. "ATM- and Cell Cycle-dependent Regulation of ATR in Response to DNA Double-strand Breaks." Nature Cell Biology 8 (2006): 37-45. Jin, J., J. Shirogane, L. Xu, G. Nalepa, J. Qin, S. J. Elledge, and J. W. Harper. "SCFβ-TRCP Links Chk1 Signaling to Degradation of the Cdc25A Protein Phosphatase." Genes & Development 17 (2003): 3062-3074. |
| 8 | 'To die or not to die' – the decision between repair and apoptosis |
Yu, J., L. Zhang, P. M. Hwang, K. W. Kinzler, and B. Vogelstein. "PUMA Induces the Rapid Apoptosis of Colorectal Cancer Cells." Molecular Cell 7 (2001): 673-82. Adimoolam, S., and J. M. Ford. "p53 and DNA Damage-inducible Expression of the Xeroderma Pigmentosum Group C Gene." Proc Natl Acad Sci U S A 99 (2002): 12985-90. |
| 9 | Structural insights into the DNA damage response |
Moreno-Herrero, F., M. de Jager, N. H. Dekker, R. Kanaar, C. Wyman, and C. Dekker. " Mesoscale Conformational Changes in the DNA-repair Complex Rad50/Mre11/Nbs1 Upon Binding DNA." Nature 437 (2005):440-3. Stucki, M., J. A. Clapperton, D. Mohammad, M. B. Yaffe, S. J. Smerdon, and S. P. Jackson. "MDC1 Directly Binds Phosphorylated Histone H2AX to Regulate Cellular Responses to DNA Double-strand Breaks." Cell 123 (2005):1213-26. |
| 10 | Field trip: visit to an MIT Biology laboratory | |
| 11 | Defective DNA damage responses and cancer |
Lam, M. H., Q. Liu, S. J. Elledge, and J. M. Rosen. "Chk1 is Haploinsufficient for Multiple Functions Critical to Tumor Suppression." Cancer Cell 6 (2004): 45-59. Ventura, A., D. G. Kirsch, M. E. McLaughlin, D. A. Tuveson, J. Grimm, L. Lintault, J. Newman, E. E. Reczek, R. Weissleder, and T. Jacks. "Restoration of p53 Function Leads to Tumour Regression In vivo." Nature 445 (2007): 661-5. |
| 12 | Checkpoint-related syndromes |
Gilad, S., L. Chessa, R. Khosravi, P. Russell, Y. Galanty, M. Piane, R. A. Gatti, T. J. Jorgensen, Y. Shiloh, and A. Bar-Shira. "Genotype-Phenotype Relationships in Ataxia-Telangiectasia and Variants." American Journal of Human Genetics 62 (1998): 551-61. Bell, D. W., J. M. Varley, T. E. Szydlo, D. H. Kang, D. C. Wahrer, K. E. Shannon, M. Lubratovich, S. J. Verselis, K. J. Isselbacher, J. F. Fraumeni, J. M. Birch, F. P. Li, J. E. Garber, and D. A. Haber. "Heterozygous Germ Line hCHK2 Mutations in Li-Fraumeni Syndrome." Science 286 (1999): 2528-31. |
| 13 | Cancer treatment based on knowledge about the DNA damage response – targeted therapeutics |
Farmer, H., N. McCabe, C. J. Lord, A. N. Tutt, D. A. Johnson, T. B. Richardson, M. Santarosa, K. J. Dillon, I. Hickson, C. Knights, N. M. Martin, S. P. Jackson, G. C. Smith, and A. Ashworth. "Targeting the DNA Repair Defect in BRCA Mutant cells as a Therapeutic Strategy." Nature 434 (2005): 917-21. Vassilev, L. T., B. T. Vu, B. Graves, D. Carvajal, F. Podlaski, Z. Filipovic, N. Kong, U.Kammlott, C. Lukacs, C. Klein, N. Fotouhi, and E. A. Liu EA. "In vivo Activation of the p53 Pathway by Small-molecule Antagonists of MDM2." Science 303 (2004): 844-8. |
| 14 | Cancer treatment based on specific mutations that "drive" malignant growth – exploiting oncogene addiction |
Druker, B. J., S. Tamura, E. Buchdunger, S. Ohno, G. M. Segal, S. Fanning, J. Zimmerman, and N. B. Lydon. "Effects of a Selective Inhibitor of the Abl Tyrosine Kinase on the Growth of Bcr-Abl Positive Cells." Nature Med 2 (1996): 561-6. Paez, J. G., et al. "EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy." Science 304 (2004): 1497-1500. |
| 15 | In-class presentations |
Suggested Readings
Bartek, J., J. Bartkova, and J. Lukas. "DNA Damage Signalling Guards Against Activated Oncogenes and Tumour Progression." Oncogene 26 (2007): 7773-9.
Bartek, J., F. Falck, and J. Lukas. "CHK2 Kinase - A Busy Messenger." Nature Reviews 2 (2001): 877-86.
Bartek, J., and J. Lukas. "DNA Damage Checkpoints: From Initiation to Recovery or Adaptation. " Curr Op Cell Biol 19 (2007) 238-45.
Hanks, S. K., and T. Hunter. "The Eukaryotic Protein Kinase Superfamily: Kinase (Catalytic) Domain Structure and Classification." FASEB Journal 9 (1995): 576-586.
Harper, J. W., and S. J. Elledge. "The DNA Damage Response: Ten Years After." Mol Cell 28 (2007): 739-45.
Kastan, M. B., and J. Bartek. "Cell-cycle Checkpoints and Cancer." Nature 432 (2004): 316-323.
Kastan, M. B., and D. Lim. "The Many Substrates and Functions of ATM." Nature Reviews: Molecular Cell Biology 1 (2000): 179-186.
Kawabe, T. "G2 Checkpoint Abrogators as Anticancer Drugs." Molecular Cancer Therapeutics 3 (2004): 513-519.
Sancar, A., L. A. Lindsey-Boltz, K. Unsal-Kacmaz, and S. Linn. "Molecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints." Ann Rev Biochem 73 (2004): 39-85.
Shiloh, Y. "ATM and Related Protein Kinases: Safeguarding Genome Integrity." Nature Reviews: Cancer 3 (2003): 155-168.
Zhou, B. S., and J. Bartek. "Targeting the Checkpoint Kinases: Chemosensitization versus Chemoprotection." Nature Reviews: Cancer 4 (2004): 1-10.
Zhou, B. S., and S. J. Elledge. "The DNA Damage Response: Putting Checkpoints in Perspective." Nature 408 (2000): 433-439.