Utz Fischer
University of Würzburg
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Publication
Featured researches published by Utz Fischer.
Cell | 1995
Utz Fischer; Jochen Huber; Wilbert C. Boelens; Lain W Mattajt; Reinhard Lührmann
HIV-1 Rev protein directs nuclear export of pre-mRNAs and mRNAs containing its binding site, the Rev response element (RRE). To define how Rev acts, we used conjugates between bovine serum albumin (BSA) and peptides comprising the Rev activation domain (BSA-R). BSA-R inhibited Rev-mediated nuclear RNA export, whereas a mutant activation domain peptide conjugate did not. BSA-R did not affect the export of mRNA, tRNA, or ribosomal subunits, but did inhibit export of 5S rRNA and spliceosomal U snRNAs. BSA-R was itself exported from the nucleus in an active, saturable manner. Thus, the Rev activation domain constitutes a nuclear export signal that redirects RRE-containing viral RNAs to a non-mRNA export pathway.
Cell | 1997
Utz Fischer; Qing Liu; Gideon Dreyfuss
Spinal muscular atrophy (SMA) is an often fatal neuromuscular disease that has been directly linked to the protein product of the Survival of Motor Neurons (SMN) gene. The SMN protein is tightly associated with a novel protein, SIP1, and together they form a complex with several spliceosomal snRNP proteins. Here we show that the SMN-SIP1 complex is associated with spliceosomal snRNAs U1 and U5 in the cytoplasm of Xenopus oocytes. Antibodies directed against the SMN-SIP1 complex strongly interfere with the cytoplasmic assembly of the common (Sm) snRNP proteins with spliceosomal snRNAs and with the import of the snRNP complex into the nucleus. Thus, the SMN-SIP1 complex is directly involved in the biogenesis of spliceosomal snRNPs. Defects in spliceosomal snRNP biogenesis may, therefore, be the cause of SMA.
Cell | 1997
Qing Liu; Utz Fischer; Fan Wang; Gideon Dreyfuss
Spinal muscular atrophy (SMA), one of the most common fatal autosomal recessive diseases, is characterized by degeneration of motor neurons and muscular atrophy. The SMA disease gene, termed Survival of Motor Neurons (SMN), is deleted or mutated in over 98% of SMA patients. The function of the SMN protein is unknown. We found that SMN is tightly associated with a novel protein, SIP1, and together they form a specific complex with several spliceosomal snRNP proteins. SMN interacts directly with several of the snRNP Sm core proteins, including B, D1-3, and E. Interestingly, SIP1 has significant sequence similarity with Brr1, a yeast protein critical for snRNP biogenesis. These findings suggest a role for SMN and SIP1 in spliceosomal snRNP biogenesis and function and provide a likely molecular mechanism for the cause of SMA.
The EMBO Journal | 1997
Ron A.M. Fouchier; Barbara Meyer; James H. Simon; Utz Fischer; Michael H. Malim
Human immunodeficiency virus type‐1 (HIV‐1) is able to infect non‐dividing cells such as tissue macrophages productively because post‐entry viral nucleoprotein complexes are specifically imported into the nucleus in the absence of mitosis. Although it has been proposed that an amino‐terminal region of the viral matrix (MA, p17Gag) protein harbors a basic‐type nuclear localization sequence (NLS) that contributes to this process, utilization of three distinct nuclear import assays failed to provide any direct supporting evidence. Instead, we found that disruption of this region (26KK→TT) reduces the rate at which the viral Gag polyprotein (p55Gag) is post‐translationally processed by the viral protease. Consistent with the fact that appropriate proteolytic processing is essential for efficient viral growth in all cell types, we also show that the 26KK→TT MA mutation is equivalently deleterious to the replication of a primary macrophage‐tropic viral isolate in cultures of non‐dividing and dividing cells. Taken together, these observations suggest that proteins other than MA supply the NLS(s) that enable HIV‐1 to infect non‐dividing cells.
Nature Structural & Molecular Biology | 2001
Philipp Selenko; Remco Sprangers; Gunter Stier; Dirk Bühler; Utz Fischer; Michael Sattler
Spinal muscular atrophy (SMA) is a common motor neuron disease that results from mutations in the Survival of Motor Neuron (SMN) gene. The SMN protein plays a crucial role in the assembly of spliceosomal uridine-rich small nuclear ribonucleoprotein (U snRNP) complexes via binding to the spliceosomal Sm core proteins. SMN contains a central Tudor domain that facilitates the SMN–Sm protein interaction. A SMA-causing point mutation (E134K) within the SMN Tudor domain prevents Sm binding. Here, we have determined the three-dimensional structure of the Tudor domain of human SMN. The structure exhibits a conserved negatively charged surface that is shown to interact with the C-terminal Arg and Gly-rich tails of Sm proteins. The E134K mutation does not disrupt the Tudor structure but affects the charge distribution within this binding site. An intriguing structural similarity between the Tudor domain and the Sm proteins suggests the presence of an additional binding interface that resembles that in hetero-oligomeric complexes of Sm proteins. Our data provide a structural basis for a molecular defect underlying SMA.
Nature Cell Biology | 2001
Gunter Meister; Dirk Bühler; Ramesh S. Pillai; Friedrich Lottspeich; Utz Fischer
The spliceosomal snRNPs U1, U2, U4 and U5 contain a common RNP structure termed the Sm core that is formed by the binding of Sm proteins onto the U snRNA. Although isolated Sm proteins assemble spontaneously onto U snRNAs in vitro, there is increasing evidence that SMN and its interactor Gemin2 are involved in this process in vivo. Here, we describe a cell-free assay system for the assembly of U snRNPs that closely reproduces in vivo conditions. Using this system, we show that assembly of U1 snRNP depends on ATP. Immunodepletion of SMN–Gemin2 from the extract abolished assembly even though the extract contained high levels of Sm proteins. An affinity-purified macromolecular SMN complex consisting of 16 components including all Sm proteins restored assembly in the immunodepleted extract. These data provide the first direct evidence that a complex containing SMN and Gemin2 mediates the active assembly of spliceosomal U snRNPs.
Trends in Cell Biology | 2002
Gunter Meister; Christian Eggert; Utz Fischer
Although many RNA-protein complexes or ribonucleoproteins (RNPs) assemble spontaneously in vitro, little is known about how they form in the environment of a living cell. Insight into RNP assembly has come unexpectedly from functional analyses of the survival motor neuron (SMN) protein, a gene product that is affected in the neuromuscular disease spinal muscular atrophy. These studies show that the assembly of spliceosomal U-rich small nuclear RNPs in vivo depends on the activity of two large protein complexes, one of which contains the SMN protein. These complexes might also facilitate the assembly of other cellular RNPs.
Cell Death & Differentiation | 2005
Utz Fischer; Klaus Schulze-Osthoff
The pathogenesis of many diseases is most closely connected with aberrantly regulated apoptotic cell death. The past 15 years have witnessed an explosion in the basic knowledge of mechanisms that regulate apoptosis and the mediators that either trigger or inhibit cell death. Consequently, great interest has emerged in devising therapeutic strategies for modulating the key molecules of life-and-death decisions. Numerous novel approaches are currently being followed employing gene therapy and antisense strategies, recombinant biologics or classical organic and combinatorial chemistry in order to target specific apoptotic regulators. Although drug development is still in its infancy, several therapeutics have progressed to clinical testing or have even been approved in record time. This review outlines the recent advances in the field of apoptosis-based therapies and explores some highlights of a very active field of drug development.
The EMBO Journal | 2002
Gunter Meister; Utz Fischer
Although spliceosomal Sm proteins can assemble spontaneously onto UsnRNA in vitro, this process requires assisting factors in vivo. SMN, the protein involved in spinal muscular atrophy, is part of a complex that contains the Sm proteins and serves as a critical factor for this reaction. Here, we have reconstituted the SMN‐dependent assembly of UsnRNPs in vitro. We demonstrate that the SMN complex is necessary and sufficient for the assembly reaction. The PRMT5 complex, previously implicated in methylation and storage of Sm proteins, interacts with the SMN complex and enhances its activity in an ATP‐dependent manner. These data uncover the SMN–PRMT5 complex as a functional entity that promotes the assisted assembly of spliceosomal UsnRNPs, and potentially other, RNA–protein complexes.
The EMBO Journal | 1993
Utz Fischer; V. Sumpter; Mitsuo Sekine; T Satoh; Reinhard Lührmann
We have investigated the nuclear transport of U1 and U5 snRNPs by microinjection studies in oocytes from Xenopus laevis using snRNP particles prepared by reconstitution in vitro. Competition studies with snRNPs showed that the Sm core domain of U1 snRNPs contains a nuclear location signal that acts independently of the m3G cap. The transport of U1 snRNP can be blocked by saturation with competitor U1 snRNPs or by U5 snRNPs, which indicates that the signals on the respective Sm core domains interact with the same transport receptors. Further, by using a minimal U1 snRNP particle reconstituted in vitro and containing only the Sm core RNP domain and lacking stem‐loops I to III of U1 RNA, we show that this is targeted actively to the nucleus, in spite of the absence of the m3G cap. This indicates that under certain conditions the NLS in the Sm core domain not only is an essential, but may also be a sufficient condition for nuclear targeting. We propose that the RNA structure of a given snRNP particle determines at least in part whether the particles m3G cap is required for nuclear transport or can be dispensed with.