Faculty

		JoAnn Sekiguchi, Ph.D. Associate Professor of Internal Medicine Associate Professor of Human Genetics sekiguch@med.umich.edu 734/764-9514
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Research Interests

Our lab studies mechanisms of DNA repair and how aberrant repair processes affect genomic stability, predisposition to cancer and immune system development. The projects in the lab are focused on characterizing the non-homologous end-joining (NHEJ) pathway of DNA double strand break repair, one of the two major pathways of double strand break repair in mammalian cells. The NHEJ factors are not only required for general DNA repair, but also play critical roles during early B and T lymphocyte development and in maintaining genomic stability. Thus, mutations in the NHEJ genes are known to cause human immunodeficiency disorders and are also associated with predisposition to cancer in human patients. We use the mouse as a model system to study the biological consequences of specific targeted mutations in the NHEJ genes and to learn more about the in vivo functions of these DNA repair factors. Previous studies of NHEJ-deficient mice have provided significant mechanistic insights into the functions of the NHEJ factors in immune system development as well as in suppressing oncogenic chromosomal events that predispose the mutant mice to lymphoid neoplasias. Currently, we are using a combination of biochemical, cellular and genetic approaches to gain additional insights into the specific functions and activities of the NHEJ factors during DNA repair and lymphocyte development. We are particularly interested further characterizing the NHEJ gene, Artemis, as recent evidence suggests that different mutations cause distinct disease outcomes in human patients. Specifically, inactivating mutations in Artemis cause a human severe combined immunodeficiency associated with extreme cellular radiosensitivity and hypomorphic mutations are associated with predisposition to lymphoid neoplasia.

Education

1987 University of California, Davis; Davis, CA - B.S., Biochemistry

1987 University of California, Davis; Davis, CA - B.A., Psychology

1996 Cornell University Graduate, School of Medical Sciences, Ph.D., Molecular Biology

Postgraduate Training

1996-1997 Research Fellow, Molecular Biology Program, Sloan-Kettering Institute; New York, NY (Mentor: Dr. Stewart Shuman, M.D., Ph.D.)

1997-2003 Research Fellow, Children's Hospital, Harvard Medical School; Boston, MA

2000-2003 Research Fellow, CBR Institute for Biomedical Research; Boston, MA
( Mentor: Dr. Frederick W. Alt, Ph.D.)

Honors and Awards

1995 Frank Lappin Horsfall, Jr. Fellowship; Sloan-Kettering Institute

1998 Young Investigator Award; FASEB Summer Conference-Nucleic Acid Enzymes

1999 Richard D. Frisbee III Foundation Fellow, Leukemia and Lymphoma Society

2002 Ranadive Endowment Award, Leukemia and Lymphoma Society

2003 Biomedical Sciences Scholar Award, University of Michigan

2004 PEW Scholar in Biomedical Sciences, PEW Charitable Trust Foundation

Recent Publications

Sekiguchi, J., Ferguson, D. O., Chen, H.T., Yang, E. M., Earle, J., Gu, Y., Frank, K. M., Whitlow, S., Xu, Y., Nussenzweig, A., and F. W. Alt (2001) Genetic interactions between ATM and non-homologous end-joining factors in genomic stability and development. Proc. Natl. Acad. Sci., USA, 98:3243-3248.

Sekiguchi, J., Whitlow, S. and F. W. Alt (2001) Increased accumulation of hybrid V(D)J joins in cells expressing truncated versus full-length RAGs. Mol. Cell, 8:1383-90.

Rooney, S., Sekiguchi, J., Zhu, C., Cheng, H.-L., Manis, J., Whitlow, S., DeVido, J., Foy, D., Lombard, D., and F. W. Alt (2002) Leaky scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice. Mol. Cell, 10:1379-1390.

Dudley, D. D., Sekiguchi, J., Zhu, C., Sadofsky, M. J., Whitlow, S., DeVido, J., Monroe, R. J., Bassing, C. H. and F. W. Alt (2003) Impaired V(D)J recombination and lymphocyte development in core RAG1-expressing mice.J. Exp. Med., 198:1439-1450.

Rooney, S., Alt, F. W., Lombard, D., Whitlow, S., Eckersdorff, M., Fleming, J., Fugmann, S., Ferguson, D. O., Schatz, D. and J. Sekiguchi (2003) Defective DNA repair and increased genomic instability in Artemis-deficient murine cells. J. Exp. Med, 197:553-565.

Sekiguchi, J., Alt, F. W., and M. A. Oettinger (2003) The mechanism of V(D)J recombination. pp. 57-78. In Molecular Biology of B cells, ed. Alt F. W. and T. Honjo, Elsevier Science, USA.

Rooney, S., Sekiguchi, J., Whitlow, S., Eckersdorff, M., Manis, J. P., Lee, C., Ferguson, D. O., and F. W. Alt (2004) Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells. Proc. Natl. Acad. Sci., USA. 101:2410-2415.

Rooney, S., Alt, F. W., Sekiguchi, J. and J. P. Manis (2005) Artemis-independent functions of DNA-dependent protein kinase in IgH class switch recombination and development. Proc. Natl. Acad. Sci., USA. In press.

Morrish, T.A., Garcia-Perez, J., L., Stamato, T. D., Taccioli, G. E., Sekiguchi, J. and J. V. Moran (2007) Endonuclease-independent LINE-1 retrotransposition at mammalian telomeres. Nature, 446:208-212.

Zha, S., Sekiguchi J., Brush J.W., Bassing C.H., and F. W. Alt (2008) Complementary functions of ATM and H2AX in development and suppression of genomic instability. Proc Natl Acad Sci, USA, 105:9302-9206.

Buis, J., Wu, Y., Deng, Y.,Leddon, J., Westfield, G., Eckersdorff, M., Sekiguchi, J., Chang, S. and D. O. Ferguson (2008) Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation. Cell, 135:85-96.

Giblin, W., Chatterji, M., Westfield, G., Theisen, B., Cheng, H.L., DeVido, J., Alt, F.W., Ferguson, D.O., Schatz, D.G. and J.M. Sekiguchi (2009) Leaky SCID and aberrant DNA rearrangements due to a hypomorphic RAG1 mutation. Blood, 113:2965-2975.

Huang, Y., Giblin, W., Kubec, M., Westfield, G., St. Charles, J., Chadde, L., Kraftson, S. and J.M. Sekiguchi (2009) Impact of a hypomorphic Artemis disease allele on lymphocyte development, DNA end processing and genome stability. J Exp Med, 206:893-908.

Wu, P.Y., Frit, P., Meesala, S., Dauvillier, S., Modesti, M., Andres, S.N., Huang, Y., Sekiguchi, J., Calsou, P., Salles, B., and M.S. Junop (2009) Structural and functional interaction between the human DNA repair proteins DNA Ligase IV and XRCC4. Mol Cell Biol, 29:3163-3172.

Dinkelman, M., Spehalski, E., Stoneham, T., Buis, J., Wu, Y., Sekiguchi, J.M. and D.O. Ferguson (2009) Multiple functions of MRN in end-joining pathways during isotype class switching. Nat Struc Mol Biol, 8:808-813.

Lab Projects

Project 1: Examine the roles of the human disease gene, Artemis, a DNA repair factor with roles in tumor suppression, immune system development, DNA double strand break repair, maintaining genomic stability and telomere maintenance. In vitro and/or in vivo analyses with a focus on mutant forms of Artemis found associated with lymphoma in human patients.

Project 2: Determine the effects of mutated forms of the RAG1/RAG2 endonuclease on immune system development, genomic stability and predisposition to tumorigenesis. In vivo analyses of specific knock-in mutations of RAG1 and RAG2 in mice.

Project 3: Examine the in vitro activities and/or in vivo functions of DNA repair enzymes related to Artemis involved in DNA interstrand crosslink resolution and potentially other repair processes.

Additional Lab Links

Department of Human Genetics