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Dr. Anton Meinhart Department of Biomolecular Mechanisms Max Planck Institute for Medical Research 69120 Heidelberg, Germany Phone: +49-(0)6221-486505 Fax: +49-(0)6221-486585 E-mail: [email protected] 28/04/1974 Wels, Austria CURRICULUM VITAE 2006 - present Research group leader, Max Planck Institute for Medical Research, Heidelberg 2004 - 2006 Project and group leader, Max Planck Institute for Medical Research, Heidelberg 2002 - 2004 PostDoc, Gene Center, University of Munich 2001 - 2002 PostDoc, Free University of Berlin 1999 - 2001 Ph.D., Free University of Berlin 1997 - 1998 Diploma thesis, Crystallography, University of Vienna, Austria and University of Cologne 1993 - 1997 Study of Mineralogy and Crystallography, University of Vienna, Austria HONORS AND FELLOWSHIPS 2003 - 2004 EMBO long term fellowship 1999 Young Scientist Award from the Faculty of Natural Science, University of Vienna 1997 - 1998 DAAD-Fellowship, Student exchange program FIELDS OF INTEREST Structure – Function relationship of RNA processing factors; Coupling of Processing machines in RNA maturation; Bacterial Toxin Antitoxin systems CURRENTLY FUNDED PROJECTS DFG Einzelantrag ME 3135/1-2 EXPERIENCE IN SUPVERSION OF DOCTORIAL CANDIDATES: Currently advisor of 2 Ph.D. thesis PUBLICATIONS (10 most important publications): Vasiljeva, L., Kim, M., Mutschler, H., Buratowski, S., and Meinhart, A. (2008). The Nrd1Nab3-Sen1 termination complex interacts with the Ser5-phosphorylated RNA polymerase II C-terminal domain. Nat. Struct. Mol. Biol. 15:795-804. Becker, R., Loll, B., and Meinhart, A. (2008). Snapshots of the RNA processing factor SCAF8 bound to different phosphorylated forms of the carboxy-terminal domain of RNA-polymerase II. J. Biol. Chem. 283:22659-22669. Khoo, S. K., Loll, B., Chan, W. T., Shoeman, R. L., Ngoo, L., Yeo, C. C., and Meinhart, A. (2007). Molecular and structural characterization of the PezAT chromosomal toxin-antitoxin system of the human pathogen Streptococcus pneumoniae. J. Biol. Chem. 282:19606-19618. Meinhart, A., Kamenski, T., Hoeppner, S., Baumli, S., and Cramer, P. (2005). A structural perspective of CTD function. Genes Dev. 19:1401-1415. Armache, K. J., Mitterweger, S., Meinhart, A., and Cramer, P. (2005). Structures of complete RNA polymerase II and its subcomplex, Rpb4/7. J. Biol. Chem. 280:7131-7134. Kamenski, T., Heilmeier, S., Meinhart, A., and Cramer, P. (2004). Structure and mechanism of RNA polymerase II CTD phosphatases. Mol. Cell 15:399-407. Meinhart, A., and Cramer, P. (2004). Recognition of RNA polymerase II carboxy-terminal domain by 3'-RNA-processing factors. Nature 430:223-226. Meinhart, A., Silberzahn, T., and Cramer, P. (2003). The mRNA transcription/processing factor Ssu72 is a potential tyrosine phosphatase. J. Biol. Chem. 278:1591715921. Meinhart, A., Blobel, J., and Cramer, P. (2003). An extended winged helix domain in general transcription factor E/IIE alpha. J. Biol. Chem. 278:48267-48274. Meinhart, A., Alonso, J. C., Strater, N., and Saenger, W. (2003). Crystal structure of the plasmid maintenance system epsilon/zeta: functional mechanism of toxin zeta and inactivation by epsilon 2 zeta 2 complex formation. Proc. Natl. Acad. Sci. USA 100:1661-1666. RESEARCH INTEREST Macromolecular Machines in eukaryotic RNA 3’-end Processing Concomitant with eukaryotic transcription, RNA undergoes extensive modification. Nuclear processes, such as capping, splicing and cleavage / polyadenylation are necessary for producing a mature RNA. These RNA processing events take place in a dynamic interplay of individual transcription and processing complexes within the transcription machinery and they are intimately coupled with each other. Whereas the general protein composition and structures of individual domains of RNA 3’-end processing factors have been elucidated, information on the three dimensional arrangements within these machines, the understanding of complex formation and the spatial and temporal coordination of these events is very limited. Our current focus is a comprehensive structural and biophysical / biochemical characterization of one of the key components of the RNA 3’-end processing machinery in Saccharomyces cerevisiae, the cleavage factor IA (CF IA). CF IA governs the spatial and temporal coordination of mRNA 3’-end processing, since it recruits the entire machinery to the site of transcription by binding to the RNA Polymerase II and is thought to recognize signal sequences at the nascent RNA. We are currently studying the assembly pathway of CF IA and want to obtain structural information of this complex to the highest resolution possible. Additionally, we are interested in the putative enzymatic polynucleotide kinase activity of CF IA and its impact on complex formation or disassembly. Ultimately, these investigations will provide new insights in how and when this complex is formed during transcription and how sequence specificity for the RNA is achieved. In a long term perspective, we will extend our investigations on macromolecular assemblies that are involved in 3’-end processing events of snRNA and snoRNA and cryptic unstable transcripts (CUTs) and transcription termination. These projects are already initiated and we have characterized how the physical link between these machines and RNA polymerase II is established. In near future we will concentrate on the entire complexes and study their structural arrangement and the kinetics of assembly and disassembly. Macromolecular Machines in bacterial genome stabilization. The second research focus is the structural and functional characterization of bacterial toxin and antitoxin systems. Bacterial Toxin-Antitoxin (TA) systems were initially discovered as genetic elements encoded from prokaryotic low-copy number plasmids, where they are involved in stable maintenance and inheritance of these mobile genetic elements. Stable maintenance is performed by a mechanism called postsegregational killing (PSK), where libration of the bacterial toxin from its cognate antitoxin eventually leads to cell death, once an offspring has lost the plasmid. These systems are of general interest for antimicrobial therapy, since any activation of these toxic proteins eventually leads to cell death. We are currently investigating the kinetics of assembly and disassembly pathway of the PezA/PezT system, which we have recently discovered to be encoded from the genome of the human pathogen Streptococcus pneumoniae. The second important scope of this project is to elucidate the still enigmatic toxic activity of this system in order to find ways of activating or deactivating this system with the ultimate goal of antimicrobial therapy. METHODS APPLIED Protein crystallography, Various biophysical techniques: Fluorescence spectroscopy, Isothermal titration Calorimetry, Circular dichroism spectroscopy, Analytical Ultracentrifugation, Dynamic Light Scattering etc., Protein chemistry, Classical Molecular Biology (E. coli, Insect cell culture and yeast);