JoAnn Sekiguchi, Ph.D.
Associate Professor of Human Genetics
Associate Professor of Internal Medicine
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.
Mason JM and JM Sekiguchi (2011) Snm1B/Apollo functions in the Fanconi anemia pathway in response to DNA interstrand crosslinks. Hum Mol Gen, 13:2549-2559.
Jacobs C, Huang Y, Masud T, Lu W, Westfield G, Giblin W and JM Sekiguchi (2011) A hypomorphic Artemis mutation leads to aberrant chromosomal rearrangements and tumorigenesis. Hum Mol Gen, 20:806-819.
Walter JE, Rucci F, Detre C, Patrizi L, Paganini T, Recher M, Keszei M, Pessach I, Lang PA, Regenass S, Giliani S, Andersson E, Sekiguchi J, Al-Herz W, Cowan MJ, Dbaibo G, ElGhazali G, Gennery AR, Pasic S, Puck JM, Malech H, DeRavin SS, Niehues T, Schuetz C, Bleesing J, Terhorst C, Alt F W and L D Notarangelo (2010) Defects of B-cell tolerance and expansion of immunoglobulin-secreting cells in RAG-dependent immunodeficiency. J Exp Med, 207:1541-1554.
Dinkelmann, M, Spehalski, E, Stoneham, T, Buis, J, Wu, Y, Sekiguchi, JM and DO Ferguson (2009) Multiple functions of MRN in end-joining pathways during isotype class switching. Nat Struc Mol Biol, 8:808-813.
Giblin W, Chatterji M, Westfield G, Theisen B, Cheng HL, DeVido J, Alt FW, Ferguson DO, Schatz DG and JM 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 JM 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 PY, Frit P, Meesala S, Dauvillier S, Modesti M, Andres SN, Huang Y, Sekiguchi J, Calsou P, Salles B, and MS Junop (2009) Structural and functional interaction between the human DNA repair proteins DNA Ligase IV and XRCC4. Mol Cell Biol, 29:3163-3172.
Zha S, Sekiguchi J, Brush JW, Bassing CH, and FW Alt (2008) Complementary functions of ATM and H2AX in development and suppression of genomic instability. Proc Natl Acad Sci, USA, 105:9302-9206.
Morrish TA, Garcia-Perez JL, Stamato TD, Taccioli GE, Sekiguchi J and JV Moran (2007) Endonuclease-independent LINE-1 retrotransposition at mammalian telomeres. Nature, 446:208-212.
Sekiguchi, J. M. and D. O. Ferguson (2006) DNA double-strand break repair: A relentless hunt uncovers new prey. Cell, 124:11-12.
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. 102:2471-2475.
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.
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.
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.