Klaus Scherrrer - Research CV#

Institut Jacques Monod, CNRS and University Paris Diderot (scherrer.klaus@ijm.univ-paris-diderot.fr)

Klaus Scherrer, actually Emeritus Director of Research of the French CNRS and Professor honoris causa of the University of Brasilia (DF) Brazil, was born on 10 Dec.1931 in Schaffhausen, Switzerland. He studied chemistry, first at the EPUL in Lausanne and then at the Swiss Institute of Technology (ETH) in Zurich and obtained, after studies in organic chemistry (L. RUZISKA, V. PRELOG, A. ESCHENMOSER) a degree in Chemical Engineering (1956). In 1961 he obtained a Ph.D. at ETH, defending a thesis in biochemistry with Carl MARTIUS on Vitamin K biosynthesis. -

At post-doctoral level, after an interlude at the Mass. General Hospital in Boston, working on allosteric effects of haemoglobin upon oxygenation, he shifted (1961) to the team of J. E. DARNELL at MIT, then a newly appointed Assistant Professor with medical training, having experience in culture of human cells, just returned from a stage at the Institut Pasteur in Paris. There Klaus Scherrer discovered 45S pre-ribosomal RNA and the basic principle of processing in RNA biosynthesis (pre-rRNA conversion into functional rRNA) and, furthermore, RNA of even higher Mr of DNA-like or messenger-like base composition. This discovery was made possible by development of an original method of RNA preparation from animal cells, combining input from several methods in use with new ideas based on chemistry; this method allowed to isolate un-degraded high Mr RNA, in contrast to concurrent attempts in with the same goal.

Leading a team studying RNA biosynthesis in eukaryotic systems in the laboratory of F. GROS (Paris), he first formulated the concept of pre-messenger RNA (pre-mRNA) in the years 1963-67, interpreting the high Mr DNA-like RNA found as precursor to mRNA, in analogy to the confirmed processing of pre-rRNA into rRNA.

Shifting to Switzerland as head of the Mol. Biol. Department at the Swiss Cancer Institute (ISREC) in LAUSANNE (1967 - 1973), he extended his research on pre-mRNA synthesis and processing to mechanisms of post-transcriptional control at messenger Ribonucleoprotein (mRNP) level, giving first experimental proof for the existence of pre-mRNA (CSH Symposium 1970) and observed cytoplasmic repression of mRNA in somatic cells.

Convinced that the mRNA by itself could not possibly include all the information necessary to regulate the long, differential post-transcriptional RNA processing and selective transport, he initiated extensive research on (pre-)messenger RNA complexes (pre-mRNP and mRNP). Along with the basic rules governing mRNP structure and function, he discovered with Nicole Granboulan a new type of highly compact particles associated to mRNPs, defined as the Prosomes, which later was found by others to be identical to the core of the 26S Proteasomes, instrumental in differential protein degradation.

From 1974 to 2001 he headed a laboratory at the Institut JACQUES MONOD of the CNRS and the University PARIS VI & VII. Working in an integrative manner on genome structure, expression and regulation, in particular of the avian globin genes, he discovered in 1981 the AT-rich linkers as a particular feature of eukaryotic genome organisation involved in matrix binding (later called MARs) of DNA. Fighting against the absurd concept of "junk DNA" he was first to propose (1985-89) the organisation of the genome in 3D, attributing to the 95% of non-coding DNA (and non-translated RNA) a role in the 3D organisation of genome and transcripts.

Between 1970 - 84 he further characterised the Prosomes, this novel cellular particle and trans-acting factor, observed as a component of mRNPs and pre-mRNPs found to constitute also the Core of the 26 S Proteasomes. The Prosomes were shown to be associated to chromatin, the Nuclear Matrix and the cytoskeleton, apparently involved in differential distribution of mRNA in time and space, controlling gene expression at RNA and protein levels. The prosome/proteasome system was proposed to act, thus, as a key mechanism in homeostasis of individual proteins involved in both, protein biosynthesis and breakdown.

More recently, in the years 1996-2004, Klaus Scherrer was able to demonstrate that the giant gene transcripts he had discovered in 1962-65 are integrated into the nuclear matrix, in particular the Globin full domain transcripts (FDTs) and serve, de facto, as structural support of the nuclear matrix, shaping the dynamic nuclear architecture as well as the transport system of individual mRNAs. Thus, finally an acceptable rationale of the existence of "giant RNAs" and the exon-intron system of pre-mRNA could be given.

Ever since his first observations in molecular biology, his interest was directed to the theoretical integration of gene controls (Cascade Regulation Hypothesis, 1968/73) and later, on their dependence on 3D Genome structure, formulating the Unified Matrix Hypothesis (UMH,1989). In 2007 he developed with J. Jost (Leipzig) the concept of Gene and Genon : an attempt to extend the Operon model to eukaryots allowing for functional and information-theoretic analysis. This became possible by strict separation of product and regulative information in gene expression. Recently in the hypothesis of the Transcription Factor Cycle (TFC, 2010) he emphasised transfer of DNA-bound factors to RNA and their eventual role in post-transcriptional regulation.

All along, his results and their interpretation were considered ikonoclastic. However, the post-genomic data of the ENCODE project (2007-2014) largely confirm those results and their theoretical extrapolation, including pervasive transcription - up to 90 % of the genome being transcribed - the large size of primary transcripts, the importance of RNA processing and post-transcriptional regulation as well as the 3D organisation of eukaryotic genomes. Paris, Mai 2014