Prof. Dr. Björn Schumacher

Research Area: Genoms Stabiltiy in Aging and Disease

Website:  http://schumacher.cecad-labs.uni-koeln.de

1. Research Background:

DNA damage contributes to cancer development and ageing. Defects in the nucleotide excision repair (NER) pathway lead to distinct human disorders that are characterized by cancer susceptibility, developmental impairments and premature ageing. It remains particularly challenging to understand the mechanisms through which genome instability impacts the pathobiology of ageing. We have established the C. elegans system to investigate how DNA damage impacts tissue ageing and how multicellular organisms respond to increasing levels of genome instability with ageing. We have uncovered a novel function of the innate immune system to mediate systemic adjustments to tissue specific DNA damage. Moreover, we have uncovered mechanisms through which longevity assurance pathways respond to DNA damage accumulation and antagonize the detrimental consequences of increasing levels of DNA damage with ageing. Our long-term goals are gaining a deeper understanding of genome maintenance and longevity assurance pathways and to develop novel intervention strategies to combat ageing-associated diseases and genetic predispositions to accelerated ageing and cancer development.

2. Research questions addresses by the group:

We are interested in understanding the fundamental mechanisms through which the gradual accumulation of DNA damage leads to aging of cells and the organism. Understanding the root causes of aging will allow developing future therapies that target the aging process in order to extend health span and prevent age-related diseases. The main focus of our work is to explore how the organism responds to the presence of DNA damage. We wish to better understand how genetic mechanisms of longevity assurance respond to genome instability and promote the functional integrity of cells and tissues. To investigate how beyond cell-autonomous DNA damage responses the organism adapts to genome instability, we are investigating systemic response mechanisms that impinge on the central maintenance pathways including DNA repair, autophagy, proteostasis, and gene expression programs.

3. Possible projects:

Non cell-autonomous DNA damage responses are increasingly emerging as important mediators of physiological adaptation to genome instability with ageing. The innate immune systems plays an important role in mediating non cell-autonomous DNA damage responses in species ranging from nematode worms to mammals. We are aiming to unravel the molecular mechanisms through which the immune system senses DNA damage. We aim to integrate the activity of immune signaling in the context of DNA damage responses. Finally, we aim to gain comprehensive insight into how DNA damage-driven immune responses orchestrate systemic adjustments in the ageing organism.

4. Applied Methods and model organisms:

We will combine cytological and genetics methodologies to gain a better understanding of functional proximity between DNA damage responses and instigators of innate immune signaling. We will primarily employ the powerful genetics of the nematode model. We will use DNA damage response mutant strains to assess the mechanistic contribution to non cell-autonomous consequences of genome instability. We will follow the contribution of DNA repair systems in coordinating cell-autonomous and non cell-autonomous DNA damage responses. We will then assess how DNA damage responses orchestrate systemic responses in distinct tissues. We will assess longevity assurance mechanisms including proteostasis and stress resistance. Finally, we will integrate the new insights gained in C. elegans into mammalian models of genome instability.

In a second project, we will investigate the role of chromatin modifications in the response to genome instability. We will particularly focus on the role of histone modifications and how they alter transcriptional responses to genotoxic stress and how they modify DNA repair activity. We will use a combination of genetic mutants and biochemical and cell biology methodologies to explore the role of epigenetic modifications in genome stability and in aging.

5. Desirable skills and qualifications:

  • Qualifications: Motivation, independent thinking, understanding of the relevant scientific literature.
  • Methods: Genetics, Cell Biology, Biochemistry, in vivo imaging, proteomics, genomics, transcriptomics
  • Model organism:C. elegans, mouse/human cell culture

6. References:

  • Edifizi D, Nolte H, Babu V, Castells-Roca L, Mueller MM, Brodesser S, Krüger M, Schumacher B. Multilayered reprogramming in response to persistent DNA damage in C. elegans. Cell Rep. 2017 Aug 29;20(9):2026-2043.
  • Ackermann L, Schell M, Pokrzywa W, Kevei É, Gartner A, Schumacher B#, Hoppe T#. E4 ligase-specific ubiquitination hubs coordinate DNA double-strand-break repair and apoptosis. Nat Struct Mol Biol. 2016 Nov;23(11):995-1002. doi: 10.1038/nsmb.3296. (#co-corresponding authors)
  • Mueller M*, Castells-Roca L*, Babu V, Ermolaeva MA, Müller RU, Frommolt P, Williams AB, Greiss S, Schneider JI, Benzing T, Schermer B, Schumacher B. DAF-16/FoxO and EGL-27/GATA promote developmental growth in response to persistent somatic DNA damage. Nat Cell Biol. 2014 Nov 24:16(12):1168–1179. doi: 10.1038/ncb3071 (*equal contribution)
  • Ermolaeva MA, Segref A, Dakhovnik A, Ou HL, Schneider JI, Utermöhlen O, Hoppe T, Schumacher B. DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature. 2013 Sep 19;501(7467):416-20. doi: 10.1038/nature12452