SFB 646: Networks in Genome Expression and Maintenance
Final Report Abstract
The Collaborative Research Centre 646 (CRC646) set out to elucidate the molecular mechanisms and processes underlying two central and highly interconnected cellular functions, namely the expression and the maintenance of eukaryotic genomes, with a special emphasis on the physical and functional coupling between such processes. The expression of the genome was the focus of research area A, which comprised studies of RNA transcription, processing, nuclear export, cellular localization, translation, and turnover. In research area B the maintenance of the genome was analyzed, which included studies of DNA packaging, silencing, replication, homologous recombination and repair. A particular focus was on research projects that bridge between these two areas and the individual processes. Over the entire funding period from 2005 to 2016 numerous discoveries were made, often in an increasingly collaborative manner, and novel findings contributed to a new molecular understanding of the above mentioned processes. Already in the early phase of the CRC646, researchers provided for example a molecular description of RNA transcription-dependent DNA damage recognition and a structural framework for the transcription by the RNA polymerase I of genes not coding for proteins, such as ribosomal rDNA. Other examples are the first structure of a DNA remodeling enzyme in complex with its substrate, the description of a yeast complex mediating mRNA localization or the elucidation of the mechanism of ribosome recycling. Later, with new project leaders new technologies and new model organisms, such as the fruitfly D. melanogaster or the nematode worm C. elegans, were introduced to the CRC646. The new technology comprised computational methods, more system-wide approaches for monitoring protein-DNA interplay or RNA metabolism, and high-resolution cryo-electron microscopy. New organisms and new technology set the stage for broader approaches, and the later projects included now the characterization of transcriptional regulatory networks, RNA-mediated heterochromatin formation and gene silencing, and the maintenance of chromatin structure by a histone chaperone. However, also the initial projects developed successfully to provide a mechanistic understanding of transcription coactivator-mediated gene regulation, transcription-coupled mRNA export, the epigenetic role of newly described DNA cytosine modifications, and of translation coupled mRNA decay. These outstanding achievements are characterized by highly collaborative efforts within the CRC646 and their scientific value is underscored by numerous publications in high ranking international journals such as Nature, Cell and Science. Most importantly, of the (difficult to select) 40 most important publications resulting from CRC646 funded projects, one half is co-authored by two or more project leaders of the CRC. As a result, a wealth of entirely novel molecular insights were gained and could often be integrated into a systemwide functional understanding. Taken together, the CRC646 successfully generated synergies and left an exceptionally positive mark not only in the scientific community but also on the growing LMU Munich campus where it is further fostering a fundamentally improved understanding of eukaryotic genome maintenance and gene expression.
Publications
-
Structure and TBP binding of the Mediator head subcomplex Med8-Med18-Med20. Nat Struct Mol Biol. 2006 Oct;13(10):895-901
Larivière L, Geiger S, Hoeppner S, Röther S, Strässer K, Cramer P
-
Bypass of DNA lesions generated during anticancer treatment with cisplatin by DNA polymerase eta. Science. 2007 Nov 9;318(5852):967-70
Alt A, Lammens K, Chiocchini C, Lammens A, Pieck JC, Kuch D, Hopfner KP, Carell T
-
CPD damage recognition by transcribing RNA polymerase II. Science. 2007 Feb 9;315(5813):859-62
Brueckner F, Hennecke U, Carell T, Cramer P
-
Functional architecture of RNA polymerase I. Cell. 2007 Dec 28;131(7):1260-72
Kuhn CD, Geiger SR, Baumli S, Gartmann M, Gerber J, Jennebach S, Mielke T, Tschochner H, Beckmann R, Cramer P
-
Structure of a Survivin-Borealin-INCENP core complex reveals how chromosomal passengers travel together. Cell. 2007 Oct 19;131(2):271-85
Jeyaprakash AA, Klein UR, Lindner D, Ebert J, Nigg EA, Conti E
-
Transcribing RNA polymerase II is phosphorylated at CTD residue serine-7. Science. 2007 Dec 14;318(5857):1780-2
Chapman RD, Heidemann M, Albert TK, Mailhammer R, Flatley A, Meisterernst M, Kremmer E, Eick D
-
A nano-positioning system for macromolecular structural analysis. Nat Methods. 2008 Nov;5(11):965-71
Muschielok A, Andrecka J, Jawhari A, Brückner F, Cramer P, Michaelis J
-
Endo-siRNAs depend on a new isoform of loquacious and target artificially introduced, high-copy sequences. EMBO J. 2009. 28(19):2932-44
Hartig JV, Esslinger S, Böttcher R, Saito K, Förstemann K
-
Structural insight into nascent polypeptide chain-mediated translational stalling. Science. 2009 Dec 4;326(5958):1412-5
Seidelt B, Innis CA, Wilson DN, Gartmann M, Armache JP, Villa E, Trabuco LG, Becker T, Mielke T, Schulten K, Steitz TA, Beckmann R
-
Structures of the tRNA export factor in the nuclear and cytosolic states. Nature. 2009 Sep 3;461(7260):60-5
Cook AG, Fukuhara N, Jinek M, Conti E
-
Uniform transitions of the general RNA polymerase II transcription complex. Nat Struct Mol Biol. 2010 Oct;17(10):1272-8
Mayer A, Lidschreiber M, Siebert M, Leike K, Söding J, Cramer P
-
Structure and mechanism of the Swi2/Snf2 remodeller Mot1 in complex with its substrate TBP. Nature. 2011. 475(7356):403-7
Wollmann P, Cui S, Viswanathan R, Berninghausen O, Wells MN, Moldt M, Witte G, Butryn A, Wendler P, Beckmann R, Auble DT, Hopfner KP
-
The Mre11:Rad50 structure shows an ATP-dependent molecular clamp in DNA double-strand break repair. Cell. 2011 Apr 1;145(1):54-66
Lammens K, Bemeleit DJ, Möckel C, Clausing E, Schele A, Hartung S, Schiller CB, Lucas M, Angermüller C, Söding J, Strässer K, Hopfner KP
-
Structural basis of highly conserved ribosome recycling in eukaryotes and archaea. Nature. 2012 Feb 22;482(7386):501-6
Becker T, Franckenberg S, Wickles S, Shoemaker CJ, Anger AM, Armache JP, Sieber H, Ungewickell C, Berninghausen O, Daberkow I, Karcher A, Thomm M, Hopfner KP, Green R, Beckmann R
-
Structure of the Mediator head module. Nature. 2012 Dec 20;492(7429):448-51
Larivière L, Plaschka C, Seizl M, Wenzeck L, Kurth F, Cramer P
-
(2013). Dynamic Readers for 5-(Hydroxy)Methylcytosine and Its Oxidized Derivatives. Cell. 2013, 152, 1146-59
Spruijt CG, Gnerlich F, Smits AH, Pfaffeneder T, Jansen PW, Bauer C, Münzel M, Wagner M, Müller M, Khan F, Eberl HC, Mensinga A, Brinkman AB, Lephikov K, Müller U, Walter J, Boelens R, van Ingen H, Leonhardt H, Carell T and Vermeulen M
-
Crystal structure of the human eIF4AIII-CWC22 complex shows how a DEAD-box protein is inhibited by a MIF4G domain. Proc Natl Acad Sci U S A. 2013, 110, E4611-4618
Buchwald, G., Schussler S., Basquin C., Le Hir H. and Conti E
-
Drosophila miR-277 controls branched-chain amino acid catabolism and affects lifespan. RNA Biol. 2013, 10(6):1042-56
Esslinger SM, Schwalb B, Helfer S, Michalik KM, Witte H, Maier KC, Martin D, Michalke B, Tresch A, Cramer P, Förstemann K
-
In vitro reconstitution of an mRNA- transport complex reveals mechanisms of assembly and motor activation. J Cell Biol. 2013 Dec 23;203(6):971-84
Heym RG, Zimmermann D, Edelmann FT, Israel L, Ökten Z, Kovar DR, Niessing D
-
Monitoring Homology Search during DNA Double-Strand Break Repair In Vivo. Mol Cell, 2013, 50, 261-272
J. Renkawitz, C. A. Lademann, M. Kalocsay, and S. Jentsch
-
Role of Cdc48/p97 as a SUMO-targeted segregase curbing Rad51-Rad52 interaction. Nat Cell Biol. 2013, 15, 526-32
Bergink S, Ammon T, Kern M, Schermelleh L, Leonhardt H and Jentsch S
-
Role of Loc1p in assembly and reorganization of nuclear ASH1 messenger ribonucleoprotein particles in yeast. Proc Natl Acad Sci U S A. 2013 Dec 24;110(52):E5049-58
Niedner A, Müller M, Moorthy BT, Jansen RP, Niessing D
-
Structural basis of histone H2A-H2B recognition by the essential chaperone FACT. Nature. 2013, 499, 111-114
Hondele M, Stuwe T, Hassler M, Halbach F, Bowman A, Zhang ET, Nijmeijer B, Kotthoff C, Rybin V, Amlacher S, Hurt E and Ladurner AG
-
Structure and subunit topology of the INO80 chromatin remodeler and its nucleosome complex. Cell. 2013, 154(6):1207-19
Tosi A, Haas C, Herzog F, Gilmozzi A, Berninghausen O, Ungewickell C, Gerhold CB, Lakomek K, Aebersold R, Beckmann R, Hopfner KP
-
Transcriptome surveillance by selective termination of non-coding RNA synthesis. Cell. 2013, 155, 1075–1087
Schulz, D., Schwalb, B., Kiesel, A., Baejen, C., Torkler, P., Gagneur, J., Söding, J. and Cramer, P.
-
Efficient chromosomal gene modification with CRISPR/cas9 and PCR-based homologous recombination donors in cultured Drosophila cells. Nucleic Acids Res. 2014, 42(11):e89
Böttcher R, Hollmann M, Merk K, Nitschko V, Obermaier C, Philippou-Massier J, Wieland I, Gaul U, Förstemann K
-
Eukaryotic and archaeal TBP and TFB/TF(II)B follow different promoter DNA bending pathways. Nucleic Acids Res. 2014 42: 6219-6231
Gietl A, Holzmeister P, Blombach F, Schulz S, von Voithenberg LV, Lamb DC, Werner F, Tinnefeld P, and Grohmann D
-
Mechanisms and principles of homology search during recombination. Nat Rev Mol Cell Biol. 2014, 15, 369-383
J. Renkawitz, C. A. Lademann, and S. Jentsch
-
Synthesis of a DNA Promoter Segment Containing All Four Epigenetic Nucleosides: 5-Methyl-, 5-Hydroxymethyl-, 5-Formyl-, and 5- Carboxy-2’-Deoxycytidine. Angew. Chem. Int. Ed. 2014, 53, 315-8
Schröder A.S., Steinbacher J., Steigenberger B., Gnerlich F.A., Schiesser S., Pfaffeneder T., Carell T.
-
Tet oxidizes thymine to 5-hydroxymethyluracil in mouse embryonic stem cell DNA. Nat Chem Biol. 2014, 10, 574-81
Pfaffeneder T, Spada F, Wagner M, Brandmayr C, Laube SK, Eisen D, Truss M, Steinbacher J, Hackner B, Kotljarova O, Schuermann D, Michalakis S, Kosmatchev O, Schiesser S, Steigenberger B, Raddaoui N, Kashiwazaki G, Müller U, Spruijt CG, Vermeulen M, Leonhardt H, Schär P, Müller M and Carell T
-
TET-mediated oxidation of methylcytosine causes TDG or NEIL glycosylase dependent gene reactivation. Nucleic Acids Res. 2014, 42, 8592-604
Müller U, Bauer C, Siegl M, Rottach A and Leonhardt H
-
Architecture of the RNA polymerase II-Mediator core initiation complex. Nature. 2015, Feb 19;518(7539):376-80
Plaschka C, Larivière L, Wenzeck L, Seizl M, Hemann M, Tegunov D, Petrotchenko EV, Borchers CH, Baumeister W, Herzog F, Villa E, Cramer P
-
Phosphorylation of TET proteins is regulated via O-GlcNAcylation by the glycosyltransferase OGT. J Biol Chem. 2015, 290, 4801-12
Bauer C, Gobel K, Nagaraj N, Colantuoni C, Wang M, Muller U, Kremmer E, Rottach A and Leonhardt H
-
Architecture of the 90S Pre-ribosome: A Structural View on the Birth of the Eukaryotic Ribosome. Cell. 2016, 166, 380-93
Kornprobst M, Turk M, Kellner N, Cheng J, Flemming D, Koš-Braun I, Koš M, Thoms M, Berninghausen O, Beckmann R, Hurt E
-
Determination of Local Chromatin Composition by CasID. Nucleus. 2016, 7, 476-484
Schmidtmann E, Anton T, Rombaut P, Herzog F and Leonhardt H
-
Structural Dynamics of the YidC:Ribosome Complex during Membrane Protein Biogenesis. Cell Rep. 2016, 17: 2943-2954
Kedrov A, Wickles S, Crevenna AH, van der Sluis EO, Buschauer R, Berninghausen O, Lamb DC, and Beckmann R
-
The cryo-EM structure of a ribosome-Ski2-Ski3-Ski8 helicase complex. Science. 2016 Dec 16;354(6318):1431-1433
Schmidt C, Kowalinski E, Shanmuganathan V, Defenouillère Q, Braunger K, Heuer A, Pech M, Namane A, Berninghausen O, Fromont-Racine M, Jacquier A, Conti E, Becker T, Beckmann R
-
Sen1 has unique structural features grafted on the architecture of the Upf1-like helicase family. EMBO J. 2017 Jun 1;36(11):1590-1604
Leonaitė B, Han Z, Basquin J, Bonneau F, Libri D, Porrua O, Conti E
-
Structure of core Mediator at 3.4 A extends transcription initiation complex model. Nature. 2017, May 11;545(7653):248-251
Nozawa, K., Schneider, T., Cramer P.
-
True equilibrium measurement of transcription factor-DNA binding affinities using automated polarization microscopy. Nat Commun. 2018 Apr 23;9(1):1605
Jung C, Bandilla P, von Reutern M, Schnepf M, Rieder S, Unnerstall U, Gaul U