JoAnn Sekiguchi, Ph.D.
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.
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.
Education and Training
|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|
|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|
Sekiguchi J, Ferguson DO, Chen HT, Yang EM, Earle J, Frank K, Whitlow S, Gu Y, Xu Y, Nussenzweig A, Alt FW. Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development. Proc Natl Acad Sci U S A, 2001 Mar 13; 98(6):3243-3248. (PMID 11248063) PMC 30638
Rooney S, Alt FW, Lombard D, Whitlow S, Eckersdorff M, Fleming J, Fugmann S, Ferguson DO, Schatz DG, Sekiguchi J. Defective DNA repair and increased genomic instability in Artemis-deficient murine cells. J Exp Med, 2003 Mar 3; 197(5):553-565. (PMID 12615897) PMC 2193825.
Dudley DD, Sekiguchi J, Zhu C, Sadofsky MJ, Whitlow S, DeVido J, Monroe RJ, Bassing CH, Alt FW. Impaired V(D)J recombination and lymphocyte development in core RAG1-expressing mice. J Exp Med, 2003 Nov 3; 198(9):1439-1450. (PMID 14581608) PMC 2194253.
Rooney S, Sekiguchi J, Whitlow S, Eckersdorff M, Manis JP, Lee C, Ferguson DO, Alt FW. Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells. Proc Natl Acad Sci U S A, 2004 Feb 24; 101(8):2410-2415. (PMID 14983023) PMC 356964.
Rooney S, Alt FW, Sekiguchi J, Manis JP. Artemis-independent functions of DNA-dependent protein kinase in Ig heavy chain class switch recombination and development. Proc Natl Acad Sci U S A, 2005 Feb 15; 102(7):2471-2475. (PMID 15699324) .PMC548986.
Morrish TA, Garcia-Perez JL, Stamato TD, Taccioli GE, Sekiguchi J, Moran JV. Endonuclease-independent LINE-1 retrotransposition at mammalian telomeres. Nature, 2007 Mar 8; 446(7132):208-212. (PMID 17344853).
Zha S, Sekiguchi J, Brush JW, Bassing CH, Alt FW. Complementary functions of ATM and H2AX in development and suppression of genomic instability. Proc Natl Acad Sci U S A, 2008 Jul 8; 105(27):9302-9306. (PMID 18599436) PMC2453730
Buis J, Wu Y, Deng Y, Leddon J, Westfield G, Eckersdorff M, Sekiguchi JM, Chang S, Ferguson DO. Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation. Cell, 2008 Oct 3; 135(1):85-96. (PMID 18854157) PMC 2645868.
Giblin W, Chatterji M, Westfield G, Masud T, Theisen B, Cheng HL, DeVido J, Alt FW, Ferguson DO, Schatz DG, Sekiguchi J. Leaky severe combined immunodeficiency and aberrant DNA rearrangements due to a hypomorphic RAG1 mutation. Blood, 2009 Mar 26; 113(13):2965-2975. (PMID 19126872) PMC 2662642
Huang Y, Giblin W, Kubec M, Westfield G, St Charles J, Chadde L, Kraftson S, Sekiguchi J. Impact of a hypomorphic Artemis disease allele on lymphocyte development, DNA end processing, and genome stability. J Exp Med, 2009 Apr 13; 206(4):893-908. (PMID 19349461) PMC 2715118.
Wu PY, Frit P, Meesala S, Dauvillier S, Modesti M, Andres SN, Huang Y, Sekiguchi J, Calsou P, Salles B, Junop MS. Structural and functional interaction between the human DNA repair proteins DNA ligase IV and XRCC4. Mol Cell Biol, 2009 Jun; 29(11):3163-3172. (PMID 19332554) PMC 2682001.
Dinkelmann M, Spehalski E, Stoneham T, Buis J, Wu Y, Sekiguchi JM, Ferguson DO. Multiple functions of MRN in end-joining pathways during isotype class switching. Nat Struct Mol Biol, 2009 Aug; 16(8):808-813. (PMID 19633670) PMC 2721910.
Walter JE, Rucci F, Patrizi L, Recher M, Regenass S, Paganini T, Keszei M, Pessach I, Lang PA, Poliani PL, Giliani S, Al-Herz W, Cowan MJ, Puck JM, Bleesing J, Niehues T, Schuetz C, Malech H, DeRavin SS, Facchetti F, Gennery AR, Andersson E, Kamani NR, Sekiguchi J, Alenezi HM, Chinen J, Dbaibo G, ElGhazali G, Fontana A, Pasic S, Detre C, Terhorst C, Alt FW, Notarangelo LD. Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency. J Exp Med, 2010 Jul 5; 207(7):1541-1554. (PMID 20547827) PMC 2901061.
Jacobs C, Huang Y, Masud T, Lu W, Westfield G, Giblin W, Sekiguchi JM. A hypomorphic Artemis human disease allele causes aberrant chromosomal rearrangements and tumorigenesis. Hum Mol Genet, 2011 Feb 15; 20(4):806-819. (PMID 21147755) PMC 3024049.
Mason JM, Sekiguchi JM. Snm1B/Apollo functions in the Fanconi anemia pathway in response to DNA interstrand crosslinks. Hum Mol Genet, 2011 Jul 1; 20(13):2549-2559. (PMID 21478198) PMC 3110000.
Chaki M, Airik R, Ghosh AK, Giles RH, Chen R, Slaats GG, Wang H, Hurd TW, Zhou W, Cluckey A, Gee HY, Ramaswami G, Hong CJ, Hamilton BA, Cervenka I, Ganji RS, Bryja V, Arts HH, van Reeuwijk J, Oud MM, Letteboer SJ, Roepman R, Husson H, Ibraghimov-Beskrovnaya O, Yasunaga T, Walz G, Eley L, Sayer JA, Schermer B, Liebau MC, Benzing T, Le Corre S, Drummond I, Janssen S, Allen SJ, Natarajan S, O'Toole JF, Attanasio M, Saunier S, Antignac C, Koenekoop RK, Ren H, Lopez I, Nayir A, Stoetzel C, Dollfus H, Massoudi R, Gleeson JG, Andreoli SP, Doherty DG, Lindstrad A, Golzio C, Katsanis N, Pape L, Abboud EB, Al-Rajhi AA, Lewis RA, Omran H, Lee EY, Wang S, Sekiguchi JM, Saunders R, Johnson CA, Garner E, Vanselow K, Andersen JS, Shlomai J, Nurnberg G, Nurnberg P, Levy S, Smogorzewska A, Otto EA, Hildebrandt F. Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell, 2012 Aug 3; 150(3):533-548. (PMID 22863007) PMC 3433835.
Xiao H, Yu Z, Wu Y, Nan J, Merry DE, Sekiguchi JM, Ferguson DO, Lieberman AP, Dressler GR. A polyglutamine expansion disease protein sequesters PTIP to attenuate DNA repair and increase genomic instability. Hum Mol Genet, 2012 Oct 1; 21(19):4225-4236. (PMID 22736030) PMC 3441122.
Books and Book Chapters
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.