DNA damage is triggered for instance by UV light of the sun, ionizing radiation as well as certain chemicals and toxins. In addition, DNA damage occurs spontaneously in cells and each cell faces several thousands of DNA-damaging lesions per day. Finally, the target induction of DNA damage by means of chemo- and radiotherapy is a fundamental principle in cancer treatments.
At the molecular level, DNA damage is sensed through specialized cellular sensor protein complexes, which bind specific DNA lesions and subsequently activate the DNA damage response. The DNA damage response can lead to different outcomes including cell cycle arrest and DNA repair, cell death / apoptosis or cellular senescence, a permanent cell proliferation block.
The DNA damage response is composed by a complex signalling network governed by the DNA-damage activated protein master kinases ATM, ATR and DNA-PK. These kinases and the DNA damage-activated kinase HIPK2 play a fundamental role in the DNA damage response, since they determine the cell fate decision-making through regulatory phosphorylation of specific substrate proteins including the central tumor suppressor p53. P53 is the most frequently mutated gene in human cancers, and p53 mutation has been linked to cancer cell resistance to therapy.
The underlying mechanisms by which cells orchestrate their response to DNA damage and how cells decide between different, opposing cell fate options, such as DNA repair and cell death, are currently still unclear. Defining and elucidating these mechanisms is a particular research interest at the institute.
Our main research activities focus on:
- DNA damage signalling & function and regulation of DNA damage-activated kinases ATM, ATR and HIPK2
- function & regulation of the tumor suppressor p53
- cell fate decision-making between DNA repair, cell death and cellular senescence
- regulation of DNA repair
- regulation of replication stress
- regulation of ferroptosis
- mechanisms of radio- and chemoresistance
- role of PML nuclear bodies in cell fate decision-making
- cellular senescence & senolysis
- identification & characterization of novel tumor markers
Our goal is to gain detailed molecular understanding of how DNA damage signals are translated into different cell fate decisions such as DNA repair versus senescence or cell death. The knowledge of the underlying molecular events may facilitate us to specifically guide the DNA damage response in cancer cells towards cell death by means of targeted manipulations.
For more detailed information on the research activities, please refer to „research informations“ under the section “Research and project groups“.