PhD Emmy Verschuren and PhD Sergey Kuznetsov selected FIMM International Group Leaders

Emmy Verschuren received her undergraduate degree in 1997 from the University of Groningenin the Netherlands. She then started graduate work in the lab of Nic Jones at the ICRF (CRUK), London, exploring mechanisms of cell death triggered by the Kaposi’s sarcoma-associated herpesvirus cyclin, K cyclin. She continued her graduate work in the lab of Gerard Evan at UCSF, San Francisco, investigating in vitro and in vivo oncogenic activities of K cyclin.

After obtaining her Ph.D. in 2003, Emmy began her postdoc with Peter Jackson at Stanford University. She here studied cell cycle control imposed by the Emi1 protein, an inhibitor of the Anaphase-Promoting Complex ubiquitin ligase, and revealed a protein stabilization/mRNA expression circuit that maintains DNA integrity and prevents cellular senescence. She then moved with Peter Jackson to Genentech Inc., South San Francisco, where her recent efforts concern the discovery of novel
cancer genes via a high-throughput senescence screen.

The Verschuren lab at FIMM will dissect cellular and biochemical properties of candidate tumor suppressors and oncogenes, aiming to build the molecular constituents of novel cancer networks. The lab will explore cell system responses to manipulation of cancer pathways, applying 3D culture and in vivo strategies. We will set up lentivirus-based gene-silencing approaches to study tumor formation in mice.

The initial focus will be on lung and breast models, and will be extended to other tissues when successful. A detailed understanding of such checkpoint responses to cancer mutations may enable us to shift responses towards apoptosis or defective checkpoint escape, and reveal new cancer prevention strategies.

Selected publications:

1. Verschuren, E.W., Ban, K.H., Masek, M.A., Lehman, N.L. and Jackson, P.K. (2007). Loss of Emi1-dependent APC/C inhibition deregulates E2F target expression and elicits DNA damageinduced senescence. Mol. Cell. Biol. 27: 7955-65.
2. Lehman, N.L., Verschuren, E.W., Hsu, J.Y., Cherry, A.M. and Jackson, P.K. (2006). Overexpression of the anaphase promoting complex/cyclosome inhibitor Emi1 leads to tetraploidy and genomic instability of p53-deficient cells. Cell Cycle. 5: 1569-73.
3. Verschuren, E.W., Hodgson, J.G., Gray, J.W., Kogan, S., Jones, N. and Evan, G.I. (2004). The role of p53 in suppression of KSHV cyclin-induced lymphomagenesis. Cancer Res., 64: 581-589.
4. Verschuren, E.W., Klefstrom, J., Evan, G.I. and Jones, N. (2002). The oncogenic potential of Kaposi’s sarcoma-associated herpesvirus cyclin is exposed by p53 loss in vitro and in vivo. Cancer Cell, 2:229-241.

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Sergey Kuznetsov received his undergraduate degree from St-Petersburg State University in Russia in 1997. He went on to study evolutionary aspects of immunity and development in the model cnidarian Hydra in the laboratory of Prof. Thomas Bosch at the University of Kiel in Germany. Upon receiving his Ph.D. in 2002, he began his postdoctoral training in the laboratory of Dr. Shyam Sharan in the Mouse Cancer Genetics Program (MCGP) at the National Cancer Institute, NIH, USA, where he worked on two DNA repair genes Rad51c and BRCA2. He generated a mouse model for Rad51c, which provided the first in vivo evidence of a role for Rad51c during meiosis as the mammalian Holliday Junction resolvase. In addition, he also developed a comprehensive in vitro system using mouse embryonic stem cells to estimate the breast cancer risk for any mutation in human BRCA2 gene.

Dr. Kuznetsov’s research team at FIMM will focus on understanding the molecular mechanisms of breast cancer progression. Using high throughput technologies, a number of candidate genes have been identified, which may be essential for breast cancer development. By studying these candidates in a mouse model, he hopes to identify the key molecules essential for different stages of mammary tumor progression and apply this knowledge to the development of new therapeutic strategies for human breast cancer.

Dr. Kuznetsov’s team will also pursue the study of the Rad51c mouse model to answer the fundamental question of why mutations in ubiquitously expressed DNA repair genes lead to tumors of certain tissues but not others. Based on his late finding that mutant Rad51c promotes tumors in specialized sebaceous glands and suppresses p53-specific tumor types, tissue-specific roles of Rad51c will be investigated in epithelial tissues in mice.

Selected publications:

1. Kuznetsov, S., et al., RAD51C deficiency in mice results in early prophase I arrest in males and sister chromatid separation at metaphase II in females. J. Cell Biol., 2007. 176(5): p. 581-592.
2. Kuznetsov, S.G., et al., Loss of Rad51c leads to embryonic lethality and tumorigenesis in mice. 2008: (submitted).
3. Kuznetsov SG, Liu P, Sharan SK. Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. Nat Med 2008;14(8):875-81.