Home Faculty and Research Faculty by Name Mark Schlissel

Mark Schlissel

Professor of Immunology and Pathogenesis*
*And Affiliate, Division of Biochemistry and Molecular Biology

Lab Homepage: http://mcb.berkeley.edu/labs/schlissel/

Full Directory Information

Research Interests

The Regulation of Antigen Receptor Gene Rearrangement and Lymphocyte Development. Immunoglobulin (Ig) and T cell receptor (TCR) genes are assembled during lymphocyte development by a novel series of highly regulated DNA rearrangement reactions known as V(D)J recombination. Understanding the regulation of gene rearrangement is important because its products (Ig and TCR molecules) control the development and function of B and T cells and because errors in the process can result in leukemia, lymphoma, or immunodeficiency disease. A single enzyme complex known as the V(D)J recombinase is required for the rearrangement of each of the seven complex genetic loci encoding antigen receptor chains. The recombinase recognizes a highly conserved DNA sequence, the RSS. Our data suggests that transcription or transcription factor binding targets the recombination reaction to a particular genetic locus at the appropriate stage of development. My lab is interested in determining the molecular basis of this link between transcription and gene rearrangement during B cell development. In addition, we are interested in the reaction mechanism of the V(D)J recombinase and the involvement of V(D)J recombination in the origin of lymphoid malignancies including leukemia and lymphoma.

Using bone marrow, thymus and fetal liver from wild-type or recombination-deficient Ig or TCR transgenic mice, we have purified primary lymphoid cells "frozen" at different stages of development. We are analyzing signal transduction pathways, patterns of transcription factor activity and chromosomal DNA-protein interactions to determine the critical receptors, protein factors and DNA sequences involved in the regulation of B and T cell development and Ig and TCR gene rearrangement. We have also devised a series of novel assays which detect recombination reaction intermediates and are using them to study both the developmental regulation and reaction mechanism of the V(D)J recombinase. Recently, we devised an in vitro assay system which recapitulates the developmental regulation of V(D)J recombination and are engaged in the dissection of its molecular components. Additional interests pursued through the above studies include the role of chromatin structure in the regulation of gene activity, the mechanisms of transcriptional enhancer activity, and the biochemistry of cell transformation.

Current Projects

Active projects in the lab include 1) an analysis of the influence of chromatin structure on the targeting of V(D)J recombination; 2) reconstitution of regulated V(D)J recombination in vitro using purified recombinase components and long DNA templates; 3) promoter and enhancer activities involved in the transcriptional regulation of genes encoding the V(D)J recombinase (RAG1 and RAG2); 4) the use of gene targeting to determine the function of various domains of RAG1 and RAG2; 5) identifying transcription factors and DNA sequences involved in the regulated activation of rearrangement at the Ig kappa locus and TCR beta locus; 6) determining the role of transcriptional enhancer sequences in the targeting of recombination and in coding joint formation; 7) elucidating the rules governing receptor editing; 8) studying the mechanism and determining the frequency of transposition events catalyzed by the recombinase during lymphocyte development; 9) determining the biological function of the proto-oncogene c-Abl in developing B cells; and 10) determining the mechanisms by which the viral oncogene v-Abl arrests B cell development and causes pre-B cell leukemia.

Selected Publications

Activation of p38 MAP kinase by DNA double-strand breaks in V(D)J recombination induces a G2/M cell cycle checkpoint. [Pedraza-Alva G, Koulnis M, Charland C, Thornton T, Clements JL, Schlissel MS, Rincon M.  (2006).  EMBO J. 25, 763-73]

Chromosomal position of a VH gene segment determines its activation and inactivation as a substrate for V(D)J recombination. [Bates, J.G., Cado, D., Nolla, H. & Schlissel, M.S.(2007)  J Exp Med 204, in the press.]

Chromosomal reinsertion of broken RSS ends during T cell development. [Curry, J.D., D. Schulz, C.J. Guidos, J.S. Danska, L. Nutter, A. Nussenzweig, and M.S. Schlissel. (2007) .J Exp Med 204:2293-2303] 

Establishment of the major compatibility complex-dependent development of CD4+ and CD8+ T cells by the Cbl family proteins. [Huang F, Kitaura Y, Jang I, Naramura M, Kole HH, Liu L, Qin H, Schlissel MS, Gu H. (2006) Immunity 25,  571-81] 

Leukemia and lymphoma: a cost of doing business for adaptive immunity. [M.S. Schlissel, C.R. Kaffer, and J.D. Curry (2006) Genes Dev 20, 1539-1544]

Single-strand recombination signal sequence nicks in vivo: evidence for a capture model of synapsis. [J.D. Curry, J.K. Geier, J.K., and M.S. Schlissel  (2005) Nat Immunol 6, 1272-1279]

Variegated transcriptional activation of the immunoglobulin k locus in pre-B cells contributes to the allelic exclusion of light-chain expression. [H.E. Liang, L.Y. Hsu, D. Cado, and M.S. Schlissel (2004) Cell 118, 19-29]

Pax5 activates immunoglobulin heavy chain V-to-DJ rearrangement in transgenic thymocytes. [L.-Y. Hsu, H.E. Liang, K. Johnson, C. Kang, and M.S. Schlissel (2004) J Exp Med 199, 825-830]

A conserved transcriptional enhancer regulates RAG gene expression in developing B cells. [L.-Y. Hsu, J. Lauring, H.E. Liang, S. Greenbaum, D. Cado, Y. Zhuang, and M.S. Schlissel (2003) Immunity 19, 105-117]

A small molecule Abl knase inhibitor induces differentiation of Abelson virus-transformed pre-B cell lines. [S. A. Muljo and M. S. Schlissel (2003) Nat Immunol 4, 31-37]

The "dispensable" portion of RAG2 is necessary for efficient V-to-DJ rearrangement during B and T cell development [H. E. Liang, L. Y. Hsu, D. Cado, L. G. Cowell, G. Kelsoe, and M. S. Schlissel (2002) Immunity 17, 639-651]

Does Artemis end the hunt for the hairpin-opening activity in V(D)J recombination? [M.S. Schlissel (2002) Cell 109, 1-4]

c-Myb binds to a sequence in the proximal region of the RAG-2 promoter and is essential for promoter activity in T-lineage cells. [Q.F. Wang, J. Lauring, and M.S. Schlissel (2000) Mol. Cell. Biol. 20, 9203-9211]

The interleukin 7 receptor is required for T cell receptor gamma locus accessibility to the V(D)J recombinase. [M. S. Schlissel, S. D. Durum, and K. Muegge (2000) J. Exp. Med. 191, 1045-1052]

Distinct factors regulate the activity of the murine RAG2 promoter in B and T cell lines. [J. Lauring and M. S. Schlissel (1999) Mol. Cell. Biol. 19, 2601-2612]

Enhancer control of V(D)J recombination at the TCRb locus: differential effects on DNA cleavage and joining. [W. M. Hempel, P. Stanhope-Baker, N. Mathieu, F. Huang, M. S. Schlissel, and P. Ferrier (1998) Genes & Devel. 12, 2305-2317]

The structure of non-hairpin coding end DNA breaks in cells undergoing V(D)J recombination. [M. S. Schlissel (1998) Mol. Cell. Biol. 18, 2029-2037]

In vivo occupancy of the k light chain enhancers in primary pro- and pre-B cells: a model for k locus activation. [A. L. Shaffer, A. Peng, and M. S. Schlissel (1997) Immunity 6, 131-143]

Cell type-specific chromatin structure determines the targeting of V(D)J recombinase activity in vitro. [P. Stanhope, K. Hudson, A. Shaffer, A. Constantinescu, and M. S. Schlissel (1996) Cell 85, 887-897]

Last Updated 2007-12-19