Mouse Models of the DNA Damage Response – University of Copenhagen

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Mouse Models of the DNA Damage Response

Chromosome instability leads to genetic alterations that can cause cancer and other diseases. To limit these alterations, cells have evolved complex mechanisms that coordinate cellular responses altogether known as the DNA Damage Response (DDR).

However, in many cases the DDR is not sufficient to protect our genomes from either exogenous or endogenous insults such as replication-born DNA damage. The overall goal of our laboratory is to increase our knowledge on the mechanisms that regulate the DDR and the consequences of their deregulation. This will help us to dissect and understand the underlying causes of a number of diseases and to identify novel therapeutic strategies.

With this purpose, we are utilizing a wide range of approaches to investigate chromosomal instability from the underlying molecular mechanisms to its ultimate consequences on health. We are using cellular-based systems to perform screenings, gain mechanistic insight and analyse cellular phenotypes in different genetic contexts.

In addition, we will generate transgenic mouse models to address the physiological impact of specific genetic alterations and, in particular, their influence on cancer and aging. For both, cellular and mouse models-based studies, we are using the novel CRISPR/Cas9 technology to efficiently manipulate the genome.

We also employ high content microscopy (HCM) as a routine approach to quantify alterations in the DDR in our different models. In addition, HCM will allow us to analyse different genetic and drug screenings that we will perform to identify novel therapeutic targets or compounds with clinical interest.

Finally, in collaboration with groups at the Center for Protein Research (CPR), we will perform a number of proteomic studies to investigate novel regulatory networks and the interplay between different proteins involved in the DDR. The most relevant findings will be validated and further characterized using mouse models.