Prof. Dr. Thomas Hofmann


DNA Damage Signaling in Cell Fate Decision-Making and Cancer

The genomes of our body cells are continuously under attack by DNA damage, which is handled by a complex protein network called the DNA damage response. Defects in the DNA damage response result in accumulation of mutations and genomic instability, which is a driving force for cancer and ageing. Cells can sense various types of DNA damage through specific sensor protein complexes and elicit a DNA damage response signaling network largely driven by the DNA damage checkpoint kinases ATM and ATR, which are activated upon DNA double-strand breaks or replicative stress, respectively.

Cells can respond to DNA damage by activating different cell fate-decisions. Whereas repairable DNA damage leads to a transient cell cycle arrest and DNA repair, irreparable DNA damage results in cellular senescence (ageing) linked to inflammation or to activation of cell death.

The molecular mechanisms by which the decision-making process is guided towards a specific cell fate-decision are largely unknown. Cancer cells typically inactivate key DNA repair and DNA damage response regulators, which disturbs the normal decision-making process and promotes cancer cell survival.

Our work is aimed at elucidating underlying molecular mechanisms driving the DNA damage-induced cell fate choice between DNA repair, cellular senescence and inflammation, and cell death.

We currently focus on novel molecular mechanisms involved in the regulation of the DNA damage kinases ATM and HIPK2, DNA double-strand break repair regulators of the Fanconi anemia/BRCA pathway and the tumour suppressor protein p53. We investigate the biomedical relevance of these mechanisms for cell fate choice between cell death, senescence and DNA repair in response to exogenously induced DNA damage (chemotherapeutic drugs, ionizing radiation, UV and foodborne mycotoxins) and endogenously induced damage such as replication stress and metabolically accumulated formaldehyde. 

Detailed understanding of the molecular mechanisms regulating cell fate control upon DNA damage will ideally enable us to identify novel vulnerabilities in cancer cells and to manipulate the cell fate decision-making in ageing and cancer.

Link to PubMed