Gender	Male
E-mail	rolf.jessberger@mssm.edu
Education and Training	P.D., University of Basel
	Postdoctorate, Stanford University Medical School
	B.S., University of Cologne
	Ph.D., University of Cologne

Jessberger Laboratory

Education and Training	P.D., University of Basel
	Postdoctorate, Stanford University Medical School
	B.S., University of Cologne
	Ph.D., University of Cologne

Jessberger Lab

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Jessberger Lab Website

Signaling in B Lymphocytes and Mast Cells
Our second area of interest is in B cell and mast cell activation and signaling pathways that are involved in these proceses. In particular, we investigate the properties and functions of a new type of protein that we have identified, SWAP-70, in cellular signaling networks. SWAP-70 was originally isolated by us from activated, mature murine B cells of mice in a biochemical screen for proteins that may be involved in immunoglobulin (Ig) class switch recombination (Borggrefe et al., 1998). In this screen, a nuclear protein complex named SWAP was purified that consists of about 6-8 polypeptides, among them SWAP-70. SWAP-70 in a unique way combines features of signaling proteins, shuttles between cytoplasmic membrane, cytoplasm and nucleus in activated B cells, but in other cells is found only at the cytoplasmic membrane and in the cytoplasm, providing for an attractive target in studying differentially regulated transport. In B cells, SWAP-70 is involved in immunoglobulin class switch recombination, in particular the switch to the IgE isotype, the "allergy isotype".

Recently, we have characterized SWAP-70 as an unusual type of PI(3)kinase-dependent, Ras-independent, Rac-interacting protein,which through its pleckstrin homology domain associates with the cytoplasmic membrane and to membrane ruffles. Determining the contribution of SWAP-70 to the function of Rac1, Rac2, or Rac3 -" key GTPases in a number of signaling pathways -" is one of our goals, along with understanding of signaling networks that act in B cell and mast cell activation. SWAP-70 carries a number of potential phosphorylation sites for several kinases, and has recently been shown by us to exist as a tyrosine-phosphorylated protein in activated cells. Our SWAP-70 deficient mice display several specific phenotypes such as deficiencies in CD40-signaling in B cells including the switch to IgE, impairment of mast cell degranulation, deficiencies in membrane actin rearrangements (ruffling) in a variety of cells, an autoimmune phenotype, hyperproliferation upon receptor signaling, migration deficiency, and elevated apoptosis in response to DNA damage (Borggrefe et al., 2001; 2002; Shinohara et al., 2002). Furthermore, like related dbl family proteins, SWAP-70 may well be considered an oncogene, a hypothesis that we are currently testing. Together, through our analysis of SWAP-70 and the specific molecules it interacts with in different cell types and upon activation of particular signaling pathways, we strive to significantly contribute to our understanding of these pathways, which ought to be highly relevant for biological phenomena such as the allergic reaction, diversification of the immune system, automimmunity, proliferation and apoptosis, and possibly malignant transformation.

Most recently, we have expanded our studies to a third project focusing on the unusually high levels of homologous recombination between adeno-associated virus (AAV) vectors and cellular DNA. As reported by D. Russell, AAV vectors may recombine with homologous sequences in the target cell at frequencies of up to one percent, several orders of magnitude higher than conventional gene targeting. There is, however, even more random, non-homologous recombination, which occurs at frequencies as high as ten percent. Our studies aim to determine factors that influence the balance between homologous and non-homologous recombination in this potentially very useful system.

DNA and Chromosome Dynamics
One of our projects aims at understanding the contribution of SMC (structural maintenance of chromosomes) proteins to DNA recombination and repair, sister chromatid cohesion, and related processes. The evolutionary highly conserved eukaryotic SMC protein family, with six members named SMC1 to SMC6, is involved in several key nucelar processes (reviews: Jessberger et al., 1998; Strunnikov and Jessberger, 1999; Jessberger, 2002). The SMC family was first defined as such in late 1994, and our publication in 1996 was the first on mammalian SMC proteins (Jessberger et al., 1996). Processes in which SMC proteins are involved are chromosome condensation, sister chromatid cohesion, DNA recombination and repair, in mitosis and meiosis. SMC proteins share a characteristic protein structure with coiled-coil-domains flanked by globular N- and C-terminal domains, and divided in the central region by a flexible hinge domainthat allows movement of the arms.

The six types of SMC proteins form three types of heterodimers: SMC1 & SMC3, SMC2 & SMC4, and SMC5 & SMC6. All the heterodimers constitute core components of larger multiprotein complexes that carry out specific, ATP-driven functions in chromosome dynamics.

Our studies concentrate on the mammalian SMC1/3 heterodimer, which is component of the sister chromatid cohesion complex cohesin and which we identified as component of the mammalian recombination complex RC-1 (Jessberger et al., 1993; 1996; Stursberg et al., 1999), furthering the hypothesis of an intimate link between cohesion and intersister recombination and repair. In particular, we work towards (i) understanding the biochemical properties of SMC proteins that enable them to function in recombinational repair, (ii) deciphering the cellular response of SMC proteins to a biological threat such as DNA damage, aging, or cell cycle arrest, (iii) delineating the multiprotein complexes that SMC proteins enter into and their respective functions, and (iv) integrating such functions into the various pathways of DNA recombination and repair. Our studies also link aspects of chromatin dynamics -" sister chromatid cohesion and segregation -" to DNA repair. They further include aspects of DNA damage signaling, for the SMC proteins become phosphorylated in the DNA damage response. It is clear that these processes are intimately linked to processes like aging or oncogensis.

In addition, we have identified a novel, meiosis-specific isoform of SMC1, called SMC1b , that is responsible for sister chromatid cohesion up to anapahase II of meiosis, and provides the first example of a cell-type specific SMC protein (Revenkova et al., 2001). Its role in meiosis and its potential failure in sterility is currently being studied biochemically and in our recently created SMC1b -deficient mouse, which shows unique and highly relevant meiotic phenotypes such as 50 percent shortened chromosomal axes, and demonstrates that SMC1b is essential for meiotic cohesion, synapsis, DNA recombination, and chromosome movements (Revenkova et al., 2004). Malfunctioning SMC1b is likely to cause chromosome missegregation in human missegregation syndromes.

Jessberger R, Riwar B, Baechtold H, Akhmedov AT. SMC proteins constitute two subunits of the mammalian recombination complex RC-1. EMBO J 1996 Aug 1; 15(15): 4061-4068.

Jessberger R, Frei C, Gasser SM. Chromosome dynamics: the SMC protein family. Curr Opin Genet Dev 1998 Apr; 8(2): 254-259.

Revenkova E, Eijpe M, Heyting B, Gross B, Jessberger R. A Novel Meiosis- Specific Isoform of Mammalian SMC1. Mol Cell Biol 2001; 21: 6984-6998.

Borggrefe T, Keshavarzi S, Gross B, Walbl M, Jessberger R. Impaired IgE response in SWAP-70 deficient mice. Europ J Immunol 2001; 21: 5667-5677.

Jessberger R. The many functions of SMC proteins in chromosome dynamics. Nat Rev Mol Cell Biol 2002 Oct; 3(10): 767-778.

Shinohara M, Terada Y, Iwamatsu A, Shinohara A, Mochizuki N, Higuchi M, Gotoh Y, Ihara S, Nagata S, Itoh H, Fukui Y, Jessberger R. SWAP-70 is a guanine-nucleotide-exchange factor that mediates signalling of membrane ruffling. Nature 2002 Apr 18; 416(6882): 759-763.

Eijpe M, Offenberg H, Jessberger R, Revenkova E, Heyting C. Meiotic cohesin REC8 marks the axial elements of rat synaptonemal complexes before cohesins SMC1beta and SMC3. J Cell Biol 2003 Mar 3; 160(5): 657-670.

Revenkova E, Eijpe M, Heyting C, Hodges CA, Hunt PA, Liebe B, Scherthan H, Jessberger R. Cohesin SMC1 beta is required for meiotic chromosome dynamics, sister chromatid cohesion and DNA recombination. Nat Cell Biol 2004 Jun; 6(6): 555-562.

Schar P, Fasi M, Jessberger R. SMC1 coordinates DNA double-strand break repair pathways. Nucleic Acids Res 2004 Jul 27; 32(13): 3921-3929.

Chiu A, Revenkova E, Jessberger R. DNA interaction and dimerization of eukaryotic SMC hinge domains. J Biol Chem 2004 Jun 18; 279(25): 26233-26242.