SFB 1036:  Cellular Surveillance and Damage Response

• Subject Area: Biology
• Term: from 2012 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 201348542

A fundamental principle of life is the ability to maintain functioning biological systems in a changing environment. To do so, organisms have developed surveillance mechanisms that monitor the integrity and functionality of their structures at all levels: from organs, tissues and cells down to individual molecules. Cellular surveillance systems sense dysfunction or damage and elicit adaptive stress responses to ensure survival. Failure or deregulation of these mechanisms is associated with aging and many diseases including cancer, neurodegeneration and inflammatory disorders. We are aiming at a mechanistic understanding of cellular stress response and surveillance pathways. This requires elucidation of how stress renders molecules, macromolecular assemblies and cellular processes damaged and dysfunctional, and how stress states and damage are sensed and signaled to elicit the appropriate response. Dozens of different quality control pathways exist within cells, making a comprehensive analysis challenging. We therefore established an CRC consortium that allows to comparatively and synergistically investigate a spectrum of different strategic elements and mechanisms employed by stress responses and repair systems. In the first two funding periods, we studied surveillance systems for DNA, RNA and proteins and the processes related to synthesis of these molecules (e.g. transcription and translation). This work generated new insights into fundamental principles at several levels, including new regulatory mechanisms that connect individual systems at the systemic level. In the third funding period, we will develop our program in two directions. First, the in-depth analysis of selected stress sensing and signaling mechanisms at the molecular and structural level. Second, the analysis of damage repair and elimination mechanisms. Here we will concentrate on protein quality control since many different cellular stress conditions impinge on protein homeostasis and the CRC 1036 has high competence in this field. Overall, through the acquisition of novel projects in defined areas and the departure of others, we are able to generate several thematic “hubs” which will increase our research strength. The CRC is embedded in the environment of the Heidelberg/Mannheim life science campus, drawing expertise from seven participating basic biology and biomedical research centers (ZMBH, BZH, COS, DKFZ, EMBL, Medical Faculties Heidelberg and Mannheim). This broad structure of the consortium will provide the basis for reaching its long-term goal of gaining comprehensive mechanistic understanding of cellular surveillance systems and damage response pathways.

• DFG Programme: Collaborative Research Centres

Current projects

• Z3 - Central tasks of the SFB (Project Head Bukau, Bernd )

Completed projects

• 01 - Transcriptional and epigenetic control by Sirtuins in response to stress (Project Heads Grummt, Ingrid ;  Voit, Renate )
• 02 - The regulation of telomere transcription to promote genomic stability (Project Head Luke, Ph.D., Brian )
• 03 - Molecular mechanisms of DNA damage-induced cell fate decisions (Project Head Hofmann, Ph.D., Thomas G. )
• 04 - Release of hCdc14B phosphatase from the nucleolus in response to DNA damage (Project Head Schiebel, Elmar )
• 05 - Stress dependent responses of mRNA 3´-end processing (Project Heads Hentze, Matthias ;  Kulozik, Ph.D., Andreas Eckhard )
• 07 - Coordination of protein synthesis and cell cycle control under stress conditions (Project Head Stoecklin, Georg )
• 08 - Interplay of Hsp70/J-domain proteins and sequestrases in organization of protein quality control and stress response in yeast (Project Heads Bukau, Bernd ;  Mogk, Axel )
• 09 - Molecular mechanism of the heat shock transcription factor Hsf1 (Project Head Mayer, Matthias Peter )
• 10 - Applying quantitative profiling and imaging methods to explore the proteolytic plasticity of protein N-termini and protein misfolding processest (Project Heads Doroudgar, Ph.D., Shirin ;  Knop, Michael )
• 11 - The role of protein O-mannosylation in ER protein quality control and cellular stress responses (Project Head Strahl, Sabine )
• 12 - Rhomboid proteases in ER-associated degradation (Project Head Lemberg, Marius )
• 13 - Stress-induced regulation of N-terminal acetylation controls proteostasis in plants (Project Heads Hell, Rüdiger ;  Wirtz, Ph.D., Markus )
• 14 - Molecular mechanisms of protein thiol oxidation in peroxide sensing and stress signaling (Project Head Dick, Tobias )
• 15 - SUMOylation in Oxidative Stress Response (Project Head Melchior, Frauke )
• 16 - Surveillance of systemic iron levels in response to stress by the hepcidin/ferroportin regulatory system (Project Head Muckenthaler, Martina )
• 17 - mTOR-dependent sensing of translation stress in Neurospora crassa (Project Head Brunner, Michael )
• 18 - Cellular stress response at centromeres (Project Head Erhardt, Ph.D., Sylvia )
• 19 - Biology and mechanisms of the translational stress signalling protein, Rqc2 (Project Head Joazeiro, Claudio )
• 20 - Inter-tissue proteostasis networks to combat α-synuclein mediated endo-lysosomal damage in C. elegans (Project Head Nussbaum-Krammer, Carmen )
• 21 - Sensing and signaling integration in the surveillance mechanisms of the spindle position checkpoint (Project Head Pereira, Gislene )
• 22 - Molecular mechanisms of ribosome associated enzymes in stress response (Project Head Sinning, Irmgard )
• 23 - Surveillance of amino acid levels by mTORC1 (Project Head Teleman, Aurelio A. )
• Z1 - Quantitative protein analysis (Project Heads Mayer, Matthias Peter ;  Ruppert, Thomas )

• Applicant Institution: Ruprecht-Karls-Universität Heidelberg
• Participating Institution: Deutsches Krebsforschungszentrum (DKFZ); European Molecular Biology Laboratory (EMBL)
• Spokesperson: Professor Dr. Bernd Bukau