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Scacchetti, A., Schauer, T., Reim, A., Apostolou, Z., Campos Sparr, A., Krause, S., Heun, P., Wierer, M., and Becker, P.B.
(IMPRS-LS students are in bold)
Elife, 2020, 9.
doi: 10.7554/eLife.56325

Drosophila SWR1 and NuA4 complexes are defined by DOMINO isoforms

Histone acetylation and deposition of H2A.Z variant are integral aspects of active transcription. In Drosophila, the single DOMINO chromatin regulator complex is thought to combine both activities via an unknown mechanism. Here we show that alternative isoforms of the DOMINO nucleosome remodeling ATPase, DOM-A and DOM-B, directly specify two distinct multi-subunit complexes. Both complexes are necessary for transcriptional regulation but through different mechanisms. The DOM-B complex incorporates H2A.V (the fly ortholog of H2A.Z) genome-wide in an ATP-dependent manner, like the yeast SWR1 complex. The DOM-A complex, instead, functions as an ATP-independent histone acetyltransferase complex similar to the yeast NuA4, targeting lysine 12 of histone H4. Our work provides an instructive example of how different evolutionary strategies lead to similar functional separation. In yeast and humans, nucleosome remodeling and histone acetyltransferase complexes originate from gene duplication and paralog specification. Drosophila generates the same diversity by alternative splicing of a single gene.


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Soni, K., Martínez-Lumbreras, S., and Sattler, M.
J Mol Biol, 2020, [Epub ahead of print].
doi: 10.1016/j.jmb.2020.05.012

Conformational dynamics from ambiguous zinc coordination in the RanBP2-type zinc finger of RBM5

The multi-domain RNA binding protein RBM5 is a molecular signature of metastasis. RBM5 regulates alternative splicing of apoptotic genes including the cell death receptor Fas and the initiator Caspase-2. The RBM5 RanBP2-type zinc finger (Zf1) is known to specifically recognize single stranded RNAs with high affinity. Here, we study the structure and conformational dynamics of the Zf1 zinc finger of human RBM5 using NMR. We show that the presence of a non-canonical cysteine in Zf1 kinetically destabilizes the protein. Metal exchange kinetics show that mutation of the cysteine establishes high affinity coordination of the zinc. Our data indicate that selection of such a structurally destabilizing mutation during the course of evolution could present an opportunity for functional adaptation of the protein.


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Schmacke, N.A., and Hornung, V.
Nature, 2020, 581, 266-267.
doi: 10.1038/d41586-020-0133


Fourth defence molecule completes antiviral line-up

Toll-like receptors can initiate an immune response when they detect signs of a viral or microbial threat. New insight into how such receptor activation drives defence programs should aid our efforts to understand autoimmune diseases.


graduationCongratulations on your PhD!


Sophia Hergenhan
Circadian Control of Leukocyte Numbers in the Circulation
RG: Christoph Scheiermann

Tugce Öz Yoldas
What prevents DNA replication between meiosis I and -II in yeast?
RG: Wolfgang Zachariae

 


 

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Yildizoglu, T., Riegler, C., Fitzgerald, J.E., and Portugues, R.
Curr Biol, 2020, [Epub ahead of print].
doi: 10.1016/j.cub.2020.04.043

A Neural Representation of Naturalistic Motion-Guided Behavior in the Zebrafish Brain

All animals must transform ambiguous sensory data into successful behavior. This requires sensory representations that accurately reflect the statistics of natural stimuli and behavior. Multiple studies show that visual motion processing is tuned for accuracy under naturalistic conditions, but the sensorimotor circuits extracting these cues and implementing motion-guided behavior remain unclear. Here we show that the larval zebrafish retina extracts a diversity of naturalistic motion cues, and the retinorecipient pretectum organizes these cues around the elements of behavior. We find that higher-order motion stimuli, gliders, induce optomotor behavior matching expectations from natural scene analyses. We then image activity of retinal ganglion cell terminals and pretectal neurons. The retina exhibits direction-selective responses across glider stimuli, and anatomically clustered pretectal neurons respond with magnitudes matching behavior. Peripheral computations thus reflect natural input statistics, whereas central brain activity precisely codes information needed for behavior. This general principle could organize sensorimotor transformations across animal species.


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Bittmann, J., Grigaitis, R., Galanti, L., Amarell, S., Wilfling, F., Matos, J., and Pfander, B.
(IMPRS-LS students are in bold)
Elife, 2020, 9.
doi: 10.7554/eLife.52459

An advanced cell cycle tag toolbox reveals principles underlying temporal control of structure-selective nucleases

Cell cycle tags allow to restrict target protein expression to specific cell cycle phases. Here, we present an advanced toolbox of cell cycle tag constructs in budding yeast with defined and compatible peak expression that allow comparison of protein functionality at different cell cycle phases. We apply this technology to the question of how and when Mus81-Mms4 and Yen1 nucleases act on DNA replication or recombination structures. Restriction of Mus81-Mms4 to M phase but not S phase allows a wildtype response to various forms of replication perturbation and DNA damage in S phase, suggesting it acts as a post-replicative resolvase. Moreover, we use cell cycle tags to reinstall cell cycle control to a deregulated version of Yen1, showing that its premature activation interferes with the response to perturbed replication. Curbing resolvase activity and establishing a hierarchy of resolution mechanisms are therefore the principal reasons underlying resolvase cell cycle regulation.


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Blessing, C., and Ladurner, A.G.
Nat Struct Mol Biol, [Epub ahead of print].
doi: 10.1038/s41594-020-0412-x

Tickling PARPs into serine action

Poly-(ADP-ribosylation) is a post-translational modification with broad roles in cell signaling. A recently reported crystal structure reveals how the accessory factor HPF1 extends the catalytic active site of PARP1 and PARP2 to promote the specific ADP-ribosylation of serine residues, a prerequisite for dynamic chromatin changes induced by DNA damage.


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Kober-Hasslacher, M., Oh-Strauß, H., Kumar, D., Soberón, V., Diehl, C., Lech, M., Engleitner, T., Katab, E., Fernandez Saiz, V., Piontek, G., Li, H., Menze, B., Ziegenhain, C., Enard, W., Rad, R., Böttcher, J.P., Anders, H.J., Rudelius, M., Schmidt-Supprian, M. (IMPRS-LS students are in bold)
J Clin Invest, 2020, [Epub ahead of print].
DOI: 10.1172/JCI124382

c-Rel gain in B cells drives germinal center reactions and autoantibody production

Single nucleotide polymorphisms and locus amplification link the NF-κB transcription factor c-Rel to human autoimmune diseases and B cell lymphomas, respectively. However, the functional consequences of enhanced c-Rel levels remain enigmatic. Here, we overexpressed c-Rel specifically in mouse B cells from BAC-transgenic gene loci and demonstrate that c-Rel protein levels linearly dictated expansion of germinal center (GC) B cells and isotype-switched plasma cells. c-Rel expression in B cells of otherwise c-Rel-deficient mice fully rescued terminal B cell differentiation, underscoring its critical B cell-intrinsic roles. Unexpectedly, in GCB cells transcription-independent regulation produced the highest c-Rel protein levels amongst B cell subsets. In c-Rel overexpressing GCB cells this caused enhanced nuclear translocation, a profoundly altered transcriptional program and increased proliferation. Finally, we provide a link between c-Rel gain and autoimmunity by showing that c-Rel overexpression in B cells caused autoantibody production and renal immune complex deposition.


graduation
Congratulations on your PhD!


Irene Riera Tur
Artificial amyloid-like aggregating proteins cause cytotoxicity in vitro and in vivo
RG: Rüdiger Klein



 

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Libicher, K., Hornberger, R., Heymann, M., and Mutschler, H.
Nat Commun, 2020, 11, 904.
doi: 10.1038/s41467-020-14694-2

In vitro self-replication and multicistronic expression of large synthetic genomes

The generation of a chemical system capable of replication and evolution is a key objective of synthetic biology. This could be achieved by in vitro reconstitution of a minimal self-sustaining central dogma consisting of DNA replication, transcription and translation. Here, we present an in vitro translation system, which enables self-encoded replication and expression of large DNA genomes under well-defined, cell-free conditions. In particular, we demonstrate self-replication of a multipartite genome of more than 116 kb encompassing the full set of Escherichia coli translation factors, all three ribosomal RNAs, an energy regeneration system, as well as RNA and DNA polymerases. Parallel to DNA replication, our system enables synthesis of at least 30 encoded translation factors, half of which are expressed in amounts equal to or greater than their respective input levels. Our optimized cell-free expression platform could provide a chassis for the generation of a partially self-replicating in vitro translation system.