Head of Research Area 2, Institute for Genome Stability in Aging and Disease, Faculty of Medicine
Prof. Dr. Björn Schumacher’s research group uses the nematode worm Caenorhabditis elegans to understand the causal role of DNA damage in aging and disease. With increasing age, damage to the genome accumulates and leads to the degeneration of cells and tissues. DNA damage thus plays a causal role in aging-associated diseases. The risk of cancer also increases with age because erroneously repaired DNA leads to mutations that can trigger cancer. Schumacher’s team has identified mechanisms that antagonize the detrimental consequences of DNA damage by maintaining tissue integrity and maximizing lifespan, even when the DNA damage cannot be repaired. The Schumacher group has also shown that DNA damage in individual cells impacts the entire organism. The systemic DNA damage responses are mediated by the immune system and increase the general stress resistance of the tissues throughout the body. These findings are particularly important for understanding progeria, disorders that result in premature aging in childhood. Premature aging is caused by congenital dysfunction of the DNA repair processes. Understanding the mechanisms by which organisms respond to accumulating DNA damage with age is pivotal for developing novel therapies to prevent aging-associated diseases and contribute to optimizing cancer treatment.
Our research: The DNA in each cell of the human body experiences many damaging influences over a lifetime. Although the cells have very effective DNA repair mechanisms, DNA damage inevitably accumulates with age. DNA damage leads to a loss of tissue function and the onset of aging-associated diseases. Prof. Björn Schumacher’s research group explores how DNA damage affects cells, tissues, and the organism as a whole. This research is important in understanding several congenital diseases caused by defects in the highly complex nucleotide excision repair pathway (NER), including the childhood progeroid (premature aging) diseases, Cockayne syndrome (CS) and trichothiodystrophy (TTD), and xeroderma pigmentosum (XP), which increases the risk of skin cancer. Better understanding of the consequences of DNA repair defects may also lead to new therapeutic options for aging-associated disorders and cancer.
Our success: Prof. Schumacher’s group has shown that organisms respond to DNA damage by activating genetic mechanisms that prolong life. The focus is on understanding how this response to DNA damage is regulated so that the organism can maximize its survival even if the DNA cannot be repaired. Schumacher’s team has already identified mechanistic links between the ge-netic aging process and the stochastic accumulation of DNA damage. Schumacher and his team have revealed a previously unknown systemic immune response in C. elegans. Their key finding is that an immune response activated in individual cells in response to DNA damage can be transmitted throughout the entire body to promote survival of the organism in the face of further stress. Prof. Björn Schumacher has been awarded the Innovation Prize from the State of North Rhine-Westphalia, holds the ERC starting grant and coordinates the European training network “CodeAge” on chronic DNA damage responses in aging.
Our goals: Understanding the fundamentals of the aging process is essential for developing new therapies. It is well-known that cancer can be the result of DNA damage. Schumacher’s team recently discovered mechanisms through which the entire body responds to DNA damage in specific cells. The organism increases its chances of survival by complex systemic physiological changes. The Schumacher group aims to investigate the regulation of these systematic responses to genome damage. The ultimate goal is to support the development of novel therapies for aging-associated diseases and rare progeroid syndromes.
Our methods/techniques: The nematode C. elegans allows scientists to gain insight into the processes of DNA repair and aging, thus revealing how cells, tissue, and the body as a whole respond to DNA damage, how the organism ages, and what mechanisms may prolong survival. The C. elegans research is complemented by extending the studies to mice to address disease-specific questions. The mouse models reflect complex diseases very well, allowing researchers to explore novel therapeutic options for humans.
Figure 1: The nematode C. elegans is a particularly important animal model for aging research. Conserved longevity assurance pathways have been revealed in C. elegans. We employ the nematode as simple metazoan model to investigate the complex response mechanisms to genome instability that in humans are linked to cancer development and aging. (Image reproduced form Schumacher & Gartner, Future Oncol 2006).
Figure 2: Diverse DNA damage lesions trigger specialized DNA damage responses.
The DNA is attacked by various genotoxic insults including reactive oxygen species (ROS) produced during cellular metabolism, alkylating agents that find application in cancer therapy, ionizing irradiation (IR), which is used for radio therapy, or ultraviolet (UV) irradiation presenting a daily threat as it is contained in sunlight. The lesions they inflict are just as diverse, since ROS usually lead to base modifications, alkylating agents give rise to interstrand crosslinks (ICLs) and DNA adducts, IR induces double strand breaks (DSBs), and UV light triggers the formation of cyclobutane pyrimidine dimers (CPDs) and 6,4-photoproducts (6,4-PPs). Cells have a repertoire to sense the different lesions and subsequently activate DNA damage checkpoints. Ultimately, cells respond by chromatin remodeling, modified transcription, fine tuning of energy metabolism, cell cycle arrest, activation of DNA repair pathways and – in case of unrepairable damage load – induction of senescence or apoptosis. (Reproduced from Wolters & Schumacher, Front Genet 2013)
Figure 3: The nucleotide excision repair (NER) defects cause cancer and aging. UV lesions and helix-distorting chemical adducts are recognized by global genome (GG-) NER or transcription coupled (TC-) NER and repaired by a multi-protein core NER complex. The clinical outcomes of GG-NER and TC-NER deficiencies are remarkably distinct: GG-NER defects lead to high susceptibility to skin cancer in Xeroderma pigmentosum (XP) patients (red), whereas TC-NER defective Cockayne syndrome (CS) patients prematurely age but remain cancer-free (grey). Mutations in the common NER pathway that both recognition mechanisms funnel into, can lead to cancer-predisposition or premature aging, depending on the effect of the particular point mutation (red-grey). (Reproduced from Schumacher, Bioessays 2009)
Figure 4: DNA damage in the C. elegans germ line. DNA damage induced by ionizing radiation can be easily visualized in the C. elegans germ line using immunofluorescent staining for RAD-51 (red), a protein that is specifically recruited to chromatin (blue) at sites of DNA damage. Recent data from our laboratory show that acute DNA damage can increase organismal stress resistance challenging the classical paradigm that DNA damage has exclusively negative effects on survival and genome stability.