CONFERENCE REPORTS 51 CHIMIA 2004, 58, No. 1/2 CONFERENCE REPORTS

Chimia 58 (2004) 51–53 © Schweizerische Chemische Gesellschaft ISSN 0009–4293

The Signer DNA-Symposium in Bern

M. Lienhard Schmitz*

Abstract: As the year 2003 was not only the 50th anniversary of the discovery of the DNA structure but also the 100th birthday of Rudolf Signer, the Department of Chemistry and Biochemistry at the University of Bern organized a Symposium on November 28th, in order to honour the pioneering work of its former faculty col- league Rudolf Signer. The invited symposium speakers covered a number of aspects related to the person and work of Rudolf Signer as well as ongoing research on the structure, function and use of DNA and nucleic acids. Keywords: DNA · Double helix · Nucleic acids · RNA · Rudolf Signer

The famous Nature paper by James from ongoing research revealing the poten- these nucleic acids within intact cells is still Watson and Francis Crick describing the tial of nucleic acids for a variety of applica- hampered by the limited stability of RNA. DNA structure marks the birth year of mod- tions including molecular diagnostics, bio- Michael Famulok presented various exper- ern molecular biology, but their work chemical catalysis, drug discovery and imental strategies to couple aptamers with would not have been possible without the therapy. reporter groups, thus allowing to monitor good X-ray diffraction data collected by The symposium was officially opened competitive binding of small molecules to Rosalind Franklin. As acknowledged by by Gerhard Jäger, the Dean of the science the RNA binding site by changes in fluo- Maurice Wilkins in his Nobel-lecture, the faculty at Bern University. Christian Leu- generation of X-ray diffraction data was mann, head of the Department for Chem- critically dependent on the high-quality istry and Biochemistry, gave a short intro- DNA provided by Rudolf Signer who was a duction into the person and work of Rudolf Professor of organic chemistry in Bern. In Signer. He highlighted his scientific addition to his contribution for the elucida- achievements and also appreciated his un- tion of the DNA structure, his important usual generosity in distributing the DNA work established DNA as a high molecular samples to interested researchers. Christian weight macromolecule. Furthermore, Leumann emphasised that the symposium Rudolf Signer was a unselfish and generous should not only serve to publicise Signer’s personality, as he offered his high-quality largely forgotten scientific contributions, DNA samples to anyone interested within but also shed light on present and ongoing the scientific community. In order to digni- research. fy the person and work of Rudolf Signer, The first scientific session chaired by the symposium speakers covered not only Jack D. Dunitz (ETH Zürich) began with a historical aspects, but also showed results talk given by Michael Famulok from the University of Bonn (Germany) entitled ‘Ri- bozymes for Drug Screening’. Michael Fa- mulok pointed out that specific target-bind- ing RNA molecules, commonly designated as aptamers, can be obtained by in vitro se- lection of combinatorial nucleic acid li- *Correspondence: PD Dr. M.L. Schmitz University of Bern braries. These RNA aptamers can be used Department of Chemistry and Biochemistry for a variety of applications including the Freiestr. 3 specific inactivation of target structures up- CH–3012 Bern Tel.: +41 31 631 43 15 on aptamer binding. While modern tech- Fax: +41 31 631 48 87 nology allows the selection and identifica- The son of Rudolf Signer, Peter Signer and his E-Mail: [email protected] tion of aptamers in a short time, the use of wife chatting with Jack Dunitz (left). CONFERENCE REPORTS 52 CHIMIA 2004, 58, No. 1/2

sistently tight curvature of nucleosome core DNA which causes it to adopt a stretched conformation in vivo to be visualized. The excess curvature of nucleosomal DNA stems predominantly from the roll rather than the tilt parameter. He observed that DNA segments bent into the minor groove are either alternately shifted or kinked, and he discussed the implications of these find- ings for transcription factor binding and gene activation. During the lunch break many of the symposium participants enjoyed a project called ‘HUGO hat Töne’ created by Daniel Schümperli, Rudolf von Steiger, and Lukas Frey. A computer translated the DNA se- quence of human chromosome 23 into a se- ries of sounds, thus creating ‘genomic’ mu- sic. DNA is not only an aesthetically pleas- ing molecule, it can also be used as a template for music. The afternoon session chaired by Hans- Beat Bürgi began with a presentation by Timothy Richmond explaining the nucleo- Matthias Meili introducing the work and life of Matthias Meili, a biochemist now working some structure. Rudolf Signer to the audience. for the ‘NZZ am Sonntag’. He is owed the merit of bringing the forgotten contribu- tions of Rudolf Signer to a broader audi- rescence emission. The approaches allowed the 147 bp of DNA wrapped around the his- ence. The science journalist Matthias Meili him to identify substances binding to the tones at a resolution of 1.9 Å. A picture reported on his research on the life and sci- HIV Rev protein and inhibiting HIV repli- showing the nucleosome in the presence of entific contributions of Rudolf Signer (M. cation. He is now using these technologies water and ions illustrated the role of water Meili, ‘Signer’s Gift – Rudolf Signer and to investigate multi-protein complexes. for the movement of DNA on the octamer DNA’, Chimia 2003, 57, 735–740). He re- The next talk by Timothy Richmond surface. While naked DNA shows a rela- ported on the scientific stations of Signer, (ETH Zürich) on ‘DNA in Chromatin’ al- tively uniform structure, the packaging of which led him as a student of Hermann lowed a fascinating view on the nucleo- DNA causes major differences in the struc- Staudinger from Zürich to Freiburg/Br. and some core. He showed the structure of his- tural organization of DNA. Richmond’s then to Bern, where he carried out his im- tones within the nucleosome octamer and high-resolution structure enabled the per- portant DNA work. In 1938, Signer pub- lished an often cited paper in Nature, where he measured the physical characteristics of native DNA, describing it as a long, high- molecular weight thread-like molecule. He also emphasised the generosity of Signer, who distributed his DNA samples to inter- ested scientists at the occasion of a meeting of the Faraday society in London. Hans Trachsel (University of Bern) talked about the regulation of gene expres- sion in ribosomes. Starting with a historical excursion, he featured the classical experi- ments he performed when using the Schreier-Staehelin in vitro translation sys- tem. This assay system directs translation of globin mRNAs in rabbit reticulocyte ex- tracts only in the presence of added initia- tion factors and was thus ideally suited to study the factors mediating translation ini- tiation. This work allowed the purification of translation initiation factors and studies on their regulation, as pointed out by the ex- ample of eIF-2 phosphorylation. Phospho- rylation of this translation initiation factor precludes its function and inhibits binding Met of the tRNAi to the small ribosomal sub- unit. The speaker then switched to ongoing research which involves investigations of translation initiation factor structures and Former coworkers of Rudolf Signer: W. Reichenberger, H. Türler and K. Naef (from left to right). closed by presenting an up-to-date model of CONFERENCE REPORTS 53 CHIMIA 2004, 58, No. 1/2

Albrecht Eschenmoser lecturing. Logos of the sponsors.

translation and its regulation in eukaryotes. logues are the tricyclo-DNAs which can (University of Bern) made some conclud- In the following talk, Robert Häner form stable Watson-Crick base-pairs with ing remarks. He acknowledged the spon- (University of Bern) featured nucleic acids other nucleic acids and have antisense sors of the symposium and also expressed as targets of destruction and objects of con- properties. They display an increased ther- his thanks to all speakers, discussion part- struction. Destruction of nucleic acids is of- mal and cellular stability and efficiently in- ners and the large and interested audience, ten desired in biomedicine, as for example terfere with splicing of the pre-mRNA en- which together made this symposium a dysregulated expression of oncogenes can coding cyclophilin A. The suitability of great success. be a cause of cancer. Robert Häner present- chimeric DNA/RNA triplex-forming Received: January 5, 2004 ed several experimental approaches which oligonucleotides for inhibition of gene ex- prevent or impair the expression of genes. pression and of so-called molecular bea- While binding of antisense RNA to the cons as biosensors was discussed. mRNA prevents efficient translation and al- In the last session with Christian Leu- so recruits RNaseH to destroy the duplex mann as chairman, Albert Eschenmoser RNA, another strategy employs sequence- (ETH Zürich and The Scripps Research In- specific RNAs coupled to a cleaver such as stitute, La Jolla, USA) gave a talk entitled the metal europium. He started the second ‘The Quest for a Chemical Etiology of Nu- part of his talk by presenting the title page cleic Acid Structure’. In other words: was of Jim Watson’s book ‘The Double Helix’ there genetic material before RNA appeared which falsely displays the famous double as an information carrier? Interest in this helix in the left-handed form. He then pre- kind of research was sparked by the early sented various methods for structural sta- experiments of Stanley Miller who showed bilisation of abasic DNA and the synthesis that some amino acids can be found after of hairpin DNA. boiling of organic compounds. Recent data The next lecture entitled ‘DNA Ana- from Miller’s laboratory also allow the the- logues for Antisense Applications and ory of a ‘cold origin of life’, as a frozen More’ was given by Christian Leumann ammonium cyanide solution stored at (University of Bern). He pointed out that –78 °C for 27 years contained a wide vari- oligonucleotides can be used for a variety ety of pyrimidines and purines. Why is RNA of applications ranging from molecular di- used in nature and not the pyranosyl isomer agnostics (gene arrays) to oligo-based ther- of RNA or pentopyranosyl-(4’,2’) oligonu- apeutics and specific catalysis of reactions. cleotides? A possible clue comes from the The speaker presented the concept of finding that pyranosyl RNA and RNAs are HNAs (hexitol nucleic acids) which con- not able to form duplexes with each other, tain a phosphorylated 1,5-anhydrohexitol which would preclude information ex- backbone and LNAs (locked nucleic acids). change between these two molecules. These These novel oligonucleotide analogues are data suggest that pyranosyl RNA is unlikely capable of recognising complementary to be the genetic material preceding RNA. DNAand RNAwith very high affinities and Therefore, the quest for a chemical etiology can be efficiently transfected into cells. An- of nucleic acid structure goes on. other class of oligodeoxynucleotide ana- Last, but not least, Hans Beat Bürgi