Genome integrity is continuously challenged by a wide range of genotoxic insults that can cause DNA damage. To counteract the deleterious consequences of genotoxic stress, all organisms have evolved a network of genome surveillance mechanisms (so called ‘checkpoints’) designed to maintain the genomic integrity. When DNA damage is beyond repair, equally sophisticated molecular networks eliminate hazardous cells by cell death or senescence. Failure of these mechanisms can destabilize the genome and have devastating consequences for human development and health.
Many genes and molecular pathways involved in different aspects of DNA damage responses have been discovered. However, given their originally seemingly separate nature, the research fields focusing on cell cycle checkpoints, DNA repair, and cell death, respectively, have evolved under relatively high degree of ’isolation’. Despite indications that these fields are in fact dealing with closely related and mutually intertwined issues, little is known about how these fundamental processes communicate and influence each other and eventually decide about the fate of cells exposed to genotoxic stress.
The key idea behind the Centre of Genotoxic Stress Research (Centre) is to combine complementary expertise of three research groups covering the fields of cell cycle regulation and livecell imaging (Jiri Lukas), DNA damage checkpoint pathways (Jiri Bartek), and cell death mechanisms (Marja Jäättelä) to study the response of mammalian cells to various genotoxic insults. The main scientific objectives include:
Identification and experimental analysis of the structure and operation of the genome surveillance network, with emphasis on functional coordination between DNA damage signaling, cell cycle checkpoints and cell death pathways.
Elucidation of the spatiotemporal aspects of genome surveillance and cell death pathways in their physiological environment – the living mammalian cell.
We study responses to various types of genotoxic stress with emphasis on some of the most lethal types of DNA damage such as the DNA double strand breaks (DSBs). These studies cover the key components of the genome maintenance network, starting from the detection and initial processing of DNA and or chromatin lesions (SENSORS), followed by transducing and amplifying the initial signals and directing the response to diverse effector pathways (TRANSDUCERS), and culminating at modulation of the key enzymatic reactions involved in major cell fate decision such as cell cycle arrest, DNA repair, chromatin restructuring, and cell death (EFFECTORS). Our ambition is to identify key issues related to each of these major components of the genome surveillance network (see the specific tasks in the "PEOPLE" section).