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Emslander, Q., Vogele, K., Braun, P., Stender, J., Willy, C., Joppich, M., Hammerl, J.A., Abele, M., Meng, C., Pichlmair, A., Ludwig, C., Bugert, J.J., Simmel, F.C., and Westmeyer, G.G.
Cell Chem Biol, 2022, online ahead of print.
doi: 10.1016/j.chembiol.2022.06.003

Cell-free production of personalized therapeutic phages targeting multidrug-resistant bacteria

Bacteriophages are potent therapeutics against biohazardous bacteria, which rapidly develop multidrug resistance. However, routine administration of phage therapy is hampered by a lack of rapid production, safe bioengineering, and detailed characterization of phages. Thus, we demonstrate a comprehensive cell-free platform for personalized production, transient engineering, and proteomic characterization of a broad spectrum of phages. Using mass spectrometry, we validated hypothetical and non-structural proteins and could also monitor the protein expression during phage assembly. Notably, a few microliters of a one-pot reaction produced effective doses of phages against enteroaggregative Escherichia coli (EAEC), Yersinia pestis, and Klebsiella pneumoniae. By co-expressing suitable host factors, we could extend the range of cell-free production to phages targeting gram-positive bacteria. We further introduce a non-genomic phage engineering method, which adds functionalities for only one replication cycle. In summary, we expect this cell-free methodology to foster reverse and forward phage engineering and customized production of clinical-grade bacteriophages.

 


 

graduationCongratulations on your PhD!

Charlotte Blessing


The role of chromatin dynamics in the DNA damage response

RG: Andreas Ladurner

 


 

The Gregori Aminoff Prize was awarded at the Royal Swedish Academy of Science's annual celebration. This year's awardees are RNA researchers Elena Conti, Patrick Cramer and Seth Darst. Conti, director and head of the research department "Structural Cell Biology" at the Max Planck Institute (MPI) of Biochemistry in Martinsried, Germany, together with her colleagues from the MPI for Multidisciplinary Sciences in Göttingen, Germany, and the Rockefeller University in New York, USA, studied the cellular systems for RNA synthesis and degradation, the two processes that together regulate the lifetime of RNA molecules. RNAs are key macromolecules that are found in all living organisms and in many viruses. Conti's work focuses on the quality control and degradation of RNA. She has studied how RNA is transformed from non-functional to functional molecules, and how, finally, they are broken down when they are no longer needed or when they are found to be defective. She has focused on the exosome, which performs several of these tasks. Her results have been highly influential and encouraged many other researchers to try new approaches. 

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J.C.O'Neill*, A.C., Uzbas*, F., Antognolli*, G., Merino*, F., Draganova, K., Jäck, A., Zhang, S., Pedini, G., Schessner, J.P., Cramer, K., Schepers, A., Metzger, F., Esgleas, M., Smialowski, P., Guerrini, R., Falk, S., Feederle, R., Freytag, S., Wang, Z., Bahlo, M., Jungmann, R., Bagni, C., Borner, G.H.H., Robertson, S.P., Hauck, S.M., and Götz, M.
* equal contribution | (IMPRS-LS predocs are in bold)
Science, 2022, 376, eabf9088.
DOI: 10.1126/science.abf9088

Spatial centrosome proteome of human neural cells uncovers disease-relevant heterogeneity

The centrosome provides an intracellular anchor for the cytoskeleton, regulating cell division, cell migration, and cilia formation. We used spatial proteomics to elucidate protein interaction networks at the centrosome of human induced pluripotent stem cell-derived neural stem cells (NSCs) and neurons. Centrosome-associated proteins were largely cell type-specific, with protein hubs involved in RNA dynamics. Analysis of neurodevelopmental disease cohorts identified a significant overrepresentation of NSC centrosome proteins with variants in patients with periventricular heterotopia (PH). Expressing the PH-associated mutant pre-mRNA-processing factor 6 (PRPF6) reproduced the periventricular misplacement in the developing mouse brain, highlighting missplicing of transcripts of a microtubule-associated kinase with centrosomal location as essential for the phenotype. Collectively, cell type-specific centrosome interactomes explain how genetic variants in ubiquitous proteins may convey brain-specific phenotypes.

 


 

graduationCongratulations on your PhD!

Marius Schneider


The long non-coding RNA "upstream to Slitrk3" (RUS) affects chromatin organization by binding to Brd2 and Smarca5  

RG: Johanna Scheuermann

 


 

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Schneider, M.F., Müller, V., Müller, S.A., Lichtenthaler, S.F., Becker, P.B., and Scheuermann, J.C.
Life Sci Alliance 5.
doi: 10.26508/lsa.202201504

LncRNA RUS shapes the gene expression program towards neurogenesis

The evolution of brain complexity correlates with an increased expression of long, noncoding (lnc) RNAs in neural tissues. Although prominent examples illustrate the potential of lncRNAs to scaffold and target epigenetic regulators to chromatin loci, only few cases have been described to function during brain development. We present a first functional characterization of the lncRNA LINC01322, which we term RUS for "RNA upstream of Slitrk3." The RUS gene is well conserved in mammals by sequence and synteny next to the neurodevelopmental gene Slitrk3. RUS is exclusively expressed in neural cells and its expression increases during neuronal differentiation of mouse embryonic cortical neural stem cells. Depletion of RUS locks neuronal precursors in an intermediate state towards neuronal differentiation resulting in arrested cell cycle and increased apoptosis. RUS associates with chromatin in the vicinity of genes involved in neurogenesis, most of which change their expression upon RUS depletion. The identification of a range of epigenetic regulators as specific RUS interactors suggests that the lncRNA may mediate gene activation and repression in a highly context-dependent manner.

 


 

graduationCongratulations on your PhD!

Daan Verhagen


A novel perspective on the in vivo chromatin landscape of Saccharomyces Cerevisiae   

RG: Felix Müller-Planitz

 


 

How does cancer arise? How does cellular composition influence tumor malignancy? These questions are profound and challenging to answer, but are crucial to understand the disease and find the right cure. Now, a German-Danish team led by Professor Matthias Mann has developed a ground-breaking technology called ‘Deep Visual Proteomics’. This method provides researchers and clinicians with a protein read-out to understand cancer at single cell-type resolution. The technology was published in the journal Nature Biotechnology and demonstrates its potential in a first application to cancer cells.

Proteins are among the most important players in a variety of diseases. Aptly referred to as the 'molecular workhorses of the cell’, their proper function often determines the fitness of a cell and that of an individual by extension. Matthias Mann explains: “When something goes wrong inside our cells and we become sick, you can be sure that proteins are involved in a wide range of different ways. Because of this, mapping the protein landscape can help us determine why a tumor could develop in a particular patient, what vulnerabilities that tumor has and also what treatment strategy might prove the most beneficial.” 

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The entire genomic material of a cell must be packed into a tiny cell nucleus in such a way, that on the one hand, it can be stored in an organized manner and, on the other hand, it can be transcribed, duplicated or repaired as needed. Different proteins are responsible for space-saving packaging, which can roll up or loop the DNA. Scientists Kikuë Tachibana and Karl Duderstadt from the Max Planck Institute of Biochemistry (MPIB) in Martinsried are investigating the exact task and function of these molecular machines. They discovered that the MCM complex plays an important role in restricting DNA loop formation and thus in the three-dimensional structure of the genome and in gene regulation. The research results were published in the scientific journal Nature.

A DNA molecule is about two meters long and still has to be packed into a tiny cell nucleus. A cell nucleus is about the size of a toner particle from a printer or a fine dust particle. How does it work? How can the genetic information be stored and packaged on the one hand, but read on the other? How is it put into loops? Packaging and unpacking are also dynamic processes that must run quickly and smoothly.

Now Kikuë Tachibana, new director of the department “Totipotency” at MPIB, and her team discovered that a protein complex well known for its function in DNA replication has an unexpected role in genome folding. “During a symposium at MPIB, it emerged that my new colleague Karl Duderstadt and I shared a common interest. We decided to join forces to use complementary approaches to investigate these initial observations at a mechanistic level”. Karl Duderstadt is head of the research group "Structure and Dynamics of Molecular Machines". 

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Jocher, G., Grass, V., Tschirner, S.K., Riepler, L., Breimann, S., Kaya, T., Oelsner, M., Hamad, M.S., Hofmann, L.I., Blobel, C.P., Schmidt-Weber, C.B., Gokce, O., Jakwerth, C.A., Trimpert, J., Kimpel, J., Pichlmair, A., and Lichtenthaler, S.F.
EMBO reports, 2022, e54305.
doi: 10.15252/embr.202154305

ADAM10 and ADAM17 promote SARS-CoV-2 cell entry and spike protein-mediated lung cell fusion

The severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) is the causative agent of COVID-19, but host cell factors contributing to COVID-19 pathogenesis remain only partly understood. We identify the host metalloprotease ADAM17 as a facilitator of SARS-CoV-2 cell entry and the metalloprotease ADAM10 as a host factor required for lung cell syncytia formation, a hallmark of COVID-19 pathology. ADAM10 and ADAM17, which are broadly expressed in the human lung, cleave the SARS-CoV-2 spike protein (S) in vitro, indicating that ADAM10 and ADAM17 contribute to the priming of S, an essential step for viral entry and cell fusion. ADAM protease-targeted inhibitors severely impair lung cell infection by the SARS-CoV-2 variants of concern alpha, beta, delta, and omicron and also reduce SARS-CoV-2 infection of primary human lung cells in a TMPRSS2 protease-independent manner. Our study establishes ADAM10 and ADAM17 as host cell factors for viral entry and syncytia formation and defines both proteases as potential targets for antiviral drug development.