Université de Strasbourg

Bruno Klaholz

Biography

Institute of Genetics and Molecular and Cellular Biology (IGBMC), University of Strasbourg

Bruno Klaholz, USIAS Fellow 2018

Dr. Bruno Klaholz studied chemistry at the University of Karlsruhe (Germany), carried out a PhD in Biochemistry and X-ray crystallography on nuclear receptors at the University of Strasbourg at the IGBMC and then began to focus on cryo-electron microscopy during his postdoctoral training at the Imperial College in London (UK). He holds the position of a French National Center for Scientific Research (CNRS) Research Director at the Centre for Integrative Biology (CBI) in the IGBMC Integrated Structural Biology Department and is Head of the French Infrastructure for Integrated Structural Biology (FRISBI) and member of the European Infrastructure for Integrated Structural Biology (Instruct-ERIC), which are both hosted at CBI/IGBMC. His research group focuses on the integrative structure-function analysis of large nucleoprotein complexes such as nuclear receptors, transcription complexes, viruses and the human ribosome. He is involved in the latest cutting-edge technologies and developments in structural biology and imaging techniques, particularly in cryo-electron microscopy and image processing that enable the study of the atomic structure of macromolecular complexes.

Bruno Klaholz received the EMBO Young Investigator Programme Award (2006), the CNRS Bronze Medal (2008), the Paul Mandel prize of the Gutenberg Circle (2009), the Richard Lounsbery Award of the French Academy of Sciences and American National Academy of Sciences (2016), the Raimond Castaing prize of the French Society of Microscopies (2017) and the CNRS Silver Medal (2018). Publications include the seminal work on the structure of the human ribosome (NAR 2014; Nature 2015; Nat Commun 2016; Nature 2017), which laid the ground for this USIAS project exploring the specialized role of rRNA modifications in different cell types.

Project - High-resolution structural analysis of rRNA modifications in specialized human ribosomes

December 2018 – January 2021

Human ribosomes are cellular nano-machineries that catalyse protein biosynthesis and carry important implications for human health. We have recently determined the first high-resolution structure of the human ribosome (Nature 2015). The aim of this project is to now address the molecular mechanisms underlying protein synthesis regulation and dysregulation in humans, and to provide mechanistic insights into the role of ribosomal RNA (rRNA) modifications and their potentiallly unique character in specialized ribosomes located in different cell types. These are entirely novel areas of investigation that we would like to develop in our group. We plan to extract ribosomes from different cell types (cancer and normal), visualise chemical modifications of rRNA and analyse molecular interactions with ribosome inhibitors by reconstituting human ribosome complexes that will be studied through cutting-edge high-resolution cryo-electron microscopy. This project will thus provide ground-breaking knowledge on the specificity of human rRNA modifications and their role in drug interactions.

The originality of this project lies in the fact that it represents the first high-resolution structural analysis and 3D localisation of chemical modifications of human ribosomal RNA in different cell types. After over a decade of sustained preparatory efforts in our group this project is now at a mature stage to explore variations of rRNA modifications in different cell types and investigate the molecular basis of specialized ribosomes. Indeed, our latest results on the high-resolution structure of the human ribosome (reaching 2.5 Å resolution locally and thus revealing side-chains and fine details such as methylations; Nature, 2017) provide a unique opportunity to gain insights into the function of rRNA modifications and analyse their differences in different cell types. The project will benefit from cutting-edge cryo-electron microscopy instrumentation installed at the Centre for Integrative Biology (CBI) IGBMC within the University of Strasbourg. The feasibility of the project is guaranteed by our unique expertise in the high-resolution structural analysis of the human ribosome.

The general significance of the project lies in the analysis of chemical modifications of the human rRNA (60S and 40S ribosomal subunits: 28S, 5S and 5.8S and 18S rRNA), which comprise methylations of nucleotide bases and ribose moieties, pseudo-uridines, acetylations, and many others. In humans, over 200 rRNA modifications have been identified but their role is essentially unknown. Interestingly, these modifications are concentrated at functionally important sites such as the peptidyl transferase centre, the decoding centre and the mRNA and tRNA binding sites of the ribosome, i.e. typically where antibiotics also bind. Moreover, modification-dependent resistances against antibiotics exist and disease-specific rRNA modifications (such as in cancer) could lead to distinctly modified ribosome populations implying specialized functions. However, the molecular basis of these mechanisms is unknown. Localising and visualising chemical modifications in the rRNA and comparing them in various human ribosomes from different cell types would therefore be a major advance in the field and could contribute to the development of new drugs.

Investissements d'Avenir