Molecular Mechanisms Of DNA Damage Signaling/Repair And Cell Death And Their Role In Cancer

Cancer arises when multiple cellular alterations cooperate to create a state of uncontrolled cellular growth. Maintenance of genomic integrity and programmed cell death (apoptosis) are two crucial cellular processes, that when disrupted, often lead to cancer and other diseases.

Our laboratory focuses on the identification and functional characterization of oncogenes and tumor suppressors that control genome integrity and apoptosis. Molecular biology, biochemistry, cellular biology, knockout mice and human biopsies are used to examine the in vivo function of these genes.

Our ongoing apoptosis projects include investigation of the in vivo effect of caspase-8 deficiency on cancer development. We have also recently observed that the E3 ligase Pirh2 ubiquitylates the oncoprotein c-Myc and targets it for proteasomal degradation. Consistent with this novel function of Pirh2 mice deficient for this protein display elevated level of c-Myc and have increased cancer risk. We are currently examining more in depth the function of Pirh2 as a tumor suppressor.

The second focus of our research program is to study the mechanisms that maintain genomic stability. We have previously generated a large panel of mice deficient for DNA damage signaling or repair proteins. These strains serve to examine the mechanisms of function of these proteins and to determine whether their loss promotes the development of cancer. Proteins we are currently studying include Brca1, Rnf8, Rnf168 and Mus81. Mechanisms that regulate the functions of these proteins and identification of their substrates are being investigated.

Through these studies and collaborations with various groups we strive to further understand the mechanisms that promote cancer development.

Graduate Student(s):

• Johnny Li

Post-Doctoral Fellows:

• Miyuki Bohgaki
• Toshiyuki Bohgaki
• Marie-Jo Halaby

Selected References:

• Hakem, A., El Ghamrasni, S., Maire, G., Lemmers, B., Karaskova, J., Perez-Ordonez, B., Sanchez, O., Squire, J. and Hakem, R. Role of Casp8 in Cytokinesis, Genomic Integrity and Cancer. Blood, In Press. 2012
• Hakem, A.,Bohgaki, M., Lemmers, B., Tai, E., Leonardo Salmena, L., Elzbieta Matysiak-Zablocki, E., Bähr, W. I. L., Karaskova, J., Boutros, P, Sheng, Y., Arrowsmith, C., Chesi, M., Bergsagel P. L., Perez-Ordonez, B., Squire, J.,  Jurisica, I., Penn, L., Sanchez, O., Benchimol, S. & Hakem, R. Pirh2 is a critical negative regulator balancing opposing p53 and c-Myc induced oncogenic pathways. PLoS Genet,  2011;7(11):e1002360.
• Bohgaki, T., Salmena, L., Matysiak-Zablocki, E., Bohgaki, M., Sanchez, O., Strasser, A., Hakem, A. and Hakem, R. Caspase-8 inactivation in T cells increases necroptosis and suppresses autoimmunity in Bim-/- mice.The Journal of Cell Biology. 2011. 195(2):277-91.
• El Ghamrasni, S., Pamidi, A., Cardoso, R., Bohgaki, M., Sethu, S., Hirao, A., Mak, T., Hande, M. P., Hakem, A., and Hakem, R. Inactivation Of Chk2 And Mus81 Leads To Impaired Lymphoctes Development, Reduced Genomic Instability And Suppression Of Cancer. PLoS Genet. 2011. 7(5): e1001385.
• Bohgaki, T., Bohgaki, M., Cardoso, R., Panier, S., Stewart, G.S., Sanchez, O., Durocher, D., Hakem, A. and Hakem, R. Genomic instability, defective spermatogenesis, immunodeficiency and cancer in a mouse model of the RIDDLE syndrome. PLoS Genet. 2011. 7(4): e1001381.
• Li, L., Halaby, M. J., Hakem, A., Cardoso, R., El Ghamrasni, S., Harding, S., Chan, N., Bristow, R., Sanchez, O., Durocher, D., Hakem, R. Rnf8 deficiency impairs class switch recombination, spermatogenis, and genomic integrity and predisposes for cancer. The Journal of Experimental Medicine. 207:983-97, 2010.
• Hakem R.DNA-damage repair; the good, the bad, and the ugly. EMBO J. 27:589-605. 2008
• Leonardo Salmena and Razqallah Hakem. Caspase-8 deficiency in T-cells leads to a lethal lymphoinfiltrative immune disease. J. Exp. Med.  2005. 202: 727-732
• McPherson JP, Lemmers B., Chahwan R., Pamidi A., Migon E., Matysiak-Zablocki E., Moynahan ME., Essers J., Hanada K., Poonepalli A., Sanchez-Sweatman O., Khokha R., Kanaar R., Jasin M., Hande MP., Hakem R. 2004. Involvement Of Mammalian Mus81 In Genome Integrity And Tumour Suppression. Science304: 1822-1826
• McPherson JP, Lemmers B., Hirao A., Hakem A., Abraham J., Migon E., Matysiak-Zablocki E., Tamblyn L., Sanchez-Sweatman O., Khokha R., Squire J., Hande MP., Mak TW, Hakem R. 2004. Collaboration of Brca1 and Chk2 in tumorigenesis. Genes Dev. 18: 1144-53
• Salmena L, Lemmers B, Hakem A, Matysiak-Zablocki E, Murakami K, Au PY, Berry DM, Tamblyn L, Shehabeldin A, Migon E, Wakeham A, Bouchard D, Yeh WC, McGlade JC, Ohashi PS, Hakem R. 2003. Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev. 17:883-95.
• Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S, Parant JM, Lozano G, Hakem R, Benchimol S. 2003. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell.112:779-91.
• Mak TW, Hakem A, McPherson JP, Shehabeldin A, Zablocki E, Migon E, Duncan GS, Bouchard D, Wakeham A, Cheung A, Karaskova J, Sarosi I, Squire J, Marth J, Hakem R. 2000. Brcal required for T cell lineage development but not TCR loci rearrangement. Nature Immunology 1:77-82
• Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, de la Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM, Mak TW. 1998 Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell. 94:339-52
• Hakem R, de la Pompa JL, Elia A, Potter J, Mak TW. 1997. Partial rescue of Brca1 (5-6) early embryonic lethality by p53 or p21 null mutation. Nature Genetics16:298-302.
• Hakem R, de la Pompa JL, Sirard C, Mo R, Woo M, Hakem A, Wakeham A, Potter J, Reitmair A, Billia F, Firpo E, Hui CC, Roberts J, Rossant J, Mak TW. 1996. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell. 85:1009-23