Prof. Dr. Björn Schumacher

Research Area: Genome Stability in Ageing, Reproduction, and Disease

Branches: Cell BiologyGeneticsMolecular Biology

Website: Schumacher Lab

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. In addition, we are interested in understanding how germline genomes are maintained to allow the indefinite perpetuation of germ cells throughout the generation. 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 ageing of cells and the organism and how, in contrast, germ cells can be immortal. Understanding the root causes of ageing will allow developing future therapies that target the ageing 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:

Our project range from molecular biology, genetics and biochemistry to computational biology and bioinformatics. The causal contribution of DNA damage not only to cancer development but evenly to the aging process has been demonstrated by progeroid (premature ageing-like) syndromes that are caused by mutations in DNA repair genes. We have established the nematode C. elegans as metazoan model to investigate the consequences of DNA repair defects that in humans cause either cancer predisposition or developmental retardation and premature aging. The research project will focus on one of the three central questions we are investigating:

  1. How is somatic maintenance adapted to the requirements of the germline?
    We discovered germline DNA damage induced systemic stress resistance (GDISR) that elevates somatic endurance when offspring generation is compromised by genome instability in germ cells. We postulate that by elevating somatic endurance, GDISR extends reproductive lifespan to allow germ cells to repair their genomes and resume offspring generation later in life. GDISR thus represents a mechanisms of the adaptation of somatic maintenance to reproductive requirements. We wish to better understand the signaling mechanisms between germ cells and somatic tissues and their role in somatic and reproductive ageing.
  2. Which processes determine somatic maintenance and thus control aging?
    DNA damage accumulation in somatic tissues is thought to cause the functional deterioration during aging. We determined that the insulin-like growth factor signalling (IIS) effector DAF-16 responds to DNA damage in somatic tissues. DAF-16 activity alleviates growth arrest and enhances DNA damage resistance in somatic tissues even in the absence of DNA repair. We propose that IIS mediates the DNA damage response (DDR) in somatic tissues and that DAF-16 activity enables developmental growth amid persistent DNA lesions and promotes maintenance of differentiated tissues through enhanced tolerance of DNA damage that accumulates with aging. Mechanistically, we determined that the conserved ERK1/2 MAPK pathway regulates the DAF-16-mediated DDR. An integrated proteomics, phospoproteomics and lipidomics analysis of the in vivo response to persistent UV-induced DNA lesions revealed a comprehensive picture of the organism’s DDR. We determined a shift in proteostasis towards autophagy, a dampening of glucose and lipid metabolism, and functionally implicate IIS, EGF-, and AMPK-like signalling. We found striking similarities between the acute response to DNA damage and the proteome of aging animals thus further supporting the underlying role of DNA damage accumulation in the aging process. Our data provide new insights into the organism’s response program to DNA damage during development and aging and suggest new intervention targets for triggering stress responses to antagonize the detrimental consequences of genome instability. In this project we wish to gain better understanding of the interactions between signalling circuits and the physiological adaptations to DNA damage accumulation during ageing.
  3. What are the underlying mechanisms for germ cell immortality?
    Genome integrity in germ cells is a prerequisite for inheritance and germline immortality. We are investigating DDR in primordial and adult germ cells. Here, we focus on investigating DNA damage checkpoints and the C. elegans p53-like CEP-1 regulates the DDR in germ cells. We uncovered somatic regulation of the quality control of germline genomes. We determined that the CEP-1/p53 response in primordial germ cells is regulated by their somatic niche cells through an FGF-like signalling circuit. The apoptotic response of adult meiotic cells is also regulated by somatic influences. Here, intestinal p38 MAPK stress signalling responds to meiotic DNA damage or to environmental stressors and regulates the apoptotic demise of compromised germ cells. We are interested in better understanding of the soma confers environmental influences to the genome quality control of germ cells. Here, we hypothesize that environmental sensing could influence the course of evolution by regulating genome inheritance. We are dissecting impacts of regulatory mechanisms in somatic and germline tissues that influence the stability of heritable genomes.

4. Applied Methods and model organisms:

  • Methods: Genetics, Cell Biology, Bioinformatics, Systems Biology, Biochemistry, in vivo imaging, proteomics, genomics, transcriptomics
  • Model organism:C. elegans, mouse, human cell culture

5. Desirable skills and qualifications:

We are seeking highly motivated and dedicated candidates. Desired qualifications range from genetics, biochemistry, and molecular biology to bioinformatics. Both wet lab and dry lab projects are available depending on the candidate.

6. References:

  • Bujarrabal A, Sendtner G, Meyer DH, Chatzinikolaou G, Stratigi G, Garinis G, Schumacher B. The DREAM complex functions as conserved master regulator of somatic DNA repair capacities. Nat Struct Mol Biol. 2023 Apr;30(4):475–488.
  • Wang S, Meyer D, Schumacher B. Inheritance of paternal DNA damage by linker histone-mediated repair restriction. Nature. 2023Jan;613(7943):365-374.
  • Soltanmohammadi N, Wang S, Schumacher B. Somatic PMK-1/p38 signaling links environmental stress to germ cell apoptosis and heritable euploidy. Nat Commun. 2022 Feb 4;13(1):701.
  • Schumacher B, Pothof J, Vijg J, Hoeijmakers JHJ. The central role of DNA damage in the ageing process. Nature. 2021 Apr;592(7856):695-703.
  • Meyer DH, Schumacher B. BiT age: A transcriptome-based aging clock near the theoretical limit of accuracy. Aging Cell. 2021 Mar 3;e13320.
  • Wang S, Meyer DH, Schumacher, B. H3K4me2 regulates the recovery of protein biosynthesis and homeostasis following DNA damage. Nat Struct Mol Biol. 2020 Dec;27(12):1165-1177.  
  • Lopes AFC, Bozek K, Herholz M, Trifunovic A, Rieckher M, Schumacher B. A C. elegans model for neurodegeneration in Cockayne syndrome. Nucleic Acids Res. 2020 Nov 4;48(19):10973-10985.
  • Ou HL, Kim CS, Uszkoreit S, Wickström SA, Schumacher B. Somatic niche cells regulate the CEP-1/p53-mediated DNA damage response in primordial germ cells. Dev Cell. 2019 Jul 22;50(2):167-183.e8.
  • 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. (#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. (*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.