The Cellular Response on DNA damage
There are two key enzymes – protein kinases ATM and ATR – that regulate the cellular response in case of DNA damage. ATM is primarily activated through DNA double-strand break (DSB), ATR trough DNA single-strand break or a blocking of the replication fork. As a damage-sensor, the protein complex MRN (MRE11/RAD50/NBS1) detects DSBs, initiates DNA repair and, hence, helps to keep the genome stable. With our research we aim at understanding the function of molecules involved in DDR.
One of these proteins is Nbs 1 (Nibrin), associated with the repair of DSBs. In cell cultures and mouse model organisms we investigate how Nbs1 interacts with enzyme ATR. Through non-invasive High Content Microscopy (hiMAC) we were able to show that a lack of Nbs1 does not necessarily lead to cell death (apoptosis), but instead induces a complex DDR. In contrast, a lack of ATR leads to apoptosis immediately. Currently, we are focusing on the impact of ATR and Nbs1 on the development of age-related diseases, including neuro(de)generation.
The Function of Poly(ADP-Ribosyl)ation
Poly(ADP-ribosyl)ation – called PARylation also – is the fasted reaction on DNA damage, especially on single-strand breaks and replication stress. Poly(ADP-Ribose) polymerase 1 (PARP1) detects the DNA damage, binds to it and provokes the building of long polymer chains (PAR). PARylation and PARP1 activity play an important role in many cellular processes as well, e.g. in transcription, chromatin remodeling, proliferation, apoptosis or inflammation and aging processes. Little is known about how target proteins sense the PAR signal and regulate DDR. We work with animal models particularly bred to investigate the biological processes regulated by PAR homeostasis and PARylation.
For brain development, neural stem cells have to be strictly controlled. The modelling of chromatin (the material which chromosomes consist of) through epigenetic mechanisms is crucial for stem cell differentiation and the development of neurons (neurogenesis). For histone acetylation, the DNA strand is “unfastened” for transcription factors to bind and decipher genes. It’s histone acetyltransferases (HAT) that promote this process and are one of the key regulators of chromatin remodeling.
If we succeed to understand the epigenetic modeling of histone status, new therapies to improve the cognitive capabilities in the elderly could be developed. We work with the inducible elimination of co-factor Trrap in mouse models to investigate the epigenetic regulation of neurogenesis and neurodegeneration. Our results show the crucial role of Trrap and HAT for balancing the self-renewal and differentiation of neuro-stem cells. They regulate maintenance and functionality of post mitotic neurons to hinder neurodegenerative processes.
* incomplete due to Data protection