This section also contains suggested readings for the course.

Required 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.