SFB 1678:  Systems-level consequences of fidelity changes in mRNA and protein biosynthesis

• Subject Area: Biology ; Medicine
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 520471345

The fidelity of cellular processes that control and execute the biosynthesis of mRNA and proteins declines with age and when challenged by external stressors. This decline results in the production of physiologically unfavorable quantities (amounts) and poor quality (e.g., erroneous sequence, altered folding, or localization) of mRNA and proteins. The work of ourselves and others has shown that this fidelity decline contributes to disease mechanisms and to age-associated physiological changes. Whereas some of the processes involved in either mRNA or protein biosynthesis have been studied at great detail for decades, an integrated, comprehensive view of the systemic consequences of fidelity decline is lacking. This Collaborative Research Centre (CRC) aims to address how fidelity changes in mRNA and protein biosynthesis collectively impact cellular and organismal functions. Recent progress in experimental technologies, computational methods and theoretical understanding make it possible to tackle this question now. We will address fidelity changes in mRNA and protein biosynthesis through a research program that will 1) characterize and quantify the consequences of fidelity alterations for the transcriptome and proteome, 2) characterize the feedback between different processes, and 3) ultimately assess how declining fidelity of mRNA and protein biosynthesis contribute to changes in cellular and organismal functions. To achieve these aims, we have assembled a team of renowned scientists with complementary expertise in molecular and cellular biology, systems and computational biology, and high-throughput molecular quantification methods. We will combine molecular and cell biological methods with approaches at a systems scale, supported by newly developed computational modelling of cellular processes, adaptive changes, and interactions. A unique aspect of our research plan is the quantitative investigation of the crosstalk between processes, such as the transmission and propagation of mRNA errors to the proteome. At the proteome level, we will quantify errors during translation, protein folding, and protein localization and investigate the mechanisms linking those changes to cell physiological endpoints, such as survival, growth rates, replicative senescence, and cellular functions. As a result, this CRC will provide systems-level understanding about cellular mechanisms determining the causes and consequences of fidelity changes. The long-term vision of our consortium is to reveal the mechanisms of how those fidelity changes contribute to human disease.

• DFG Programme: Collaborative Research Centres
• International Connection: Switzerland

Current projects

• A01 - Transcript quality effects of RNAPII speed variation (Project Heads Beyer, Andreas ;  Müller, Roman-Ulrich )
• A02 - Maintaining gene expression fidelity in response to DNA- and RNA-protein crosslinks (Project Heads Beli, Petra ;  Papantonis, Argyris )
• A03 - The role of chromatin structure regulation in the susceptibility to transcription-blocking lesions (Project Head Schumacher, Björn )
• A04 - Consequences of age-related G-quadruplex formation for the fidelity of mammalian transcription (Project Head Hänsel-Hertsch, Ph.D., Robert )
• A05 - Regulation of splicing fidelity in response to DNA double-strand breaks (Project Head Panier, Stephanie )
• A06 - Regulation of alternative polyadenylation by RNA-binding proteins in senescence (Project Head Huppertz, Ina )
• A07 - Speed vs. fidelity: The role of nuclear RNA export under cellular stress (Project Heads Mayer, Andreas ;  Tresch, Achim )
• A08 - Impact of nonsense-mediated mRNA decay on gene expression fidelity (Project Head Gehring, Niels H. )
• B01 - Clearance of defective mRNA by-products by the ribosome-associated quality control pathway in stress and disease (Project Head Broch Trentini Schmidt, Ph.D., Débora )
• B02 - Coordination of endoplasmic reticulum-associated fidelity machines (Project Head Hoppe, Thorsten )
• B03 - Stress-dependent regulation of organellar proteome plasticity by dynamic selection of different translation initiation sites (Project Head Riemer, Jan )
• B04 - Chronic stress-associated alterations of translation fidelity (Project Heads Ignatova, Zoya ;  Tresch, Achim )
• B05 - Predicting the impact of biosynthetic fidelity on protein folding (Project Heads Beyer, Andreas ;  Picotti, Paola )
• B06 - Defining the interplay between RNA and protein toxicity in C9orf72-related amyotrophic lateral sclerosis (ALS) (Project Head Vilchez, David )
• B07 - Protein targeting and safeguarding upon oxidative unfolding stress (Project Head Ulrich, Kathrin )
• B08 - Metabolic signaling as a safeguard of translational fidelity (Project Heads Ignatova, Zoya ;  Weith, Matthias )
• CP01 - Administration, communication, dissemination (Project Head Beyer, Andreas )
• CP02 - Quantitative Proteomics (Project Head Krüger, Marcus )
• INF - Information Infrastructure Project: Scientific data management and data analytics (Project Heads Beyer, Andreas ;  Tresch, Achim )
• MGK - Integrated Research Training Group (Project Head Schumacher, Björn )

• Applicant Institution: Universität zu Köln
• Participating University: ETH Zürich; Georg-August-Universität Göttingen; Johannes Gutenberg-Universität Mainz; Universität Hamburg
• Participating Institution: Max-Planck-Institut für Biologie des Alterns; Max-Planck-Institut für molekulare Genetik (MPIMG)
• Spokesperson: Professor Dr. Andreas Beyer