Chromatin and DNA repair

Principal investigator
Prof.dr. Haico van Attikum

The DNA damage response (DDR) is a network of cellular pathways that sense, signal and repair DNA lesions. Defects in the DDR can result in mutations and genome instability, and can lead to diseases such as cancer, immunodeficiency and neurodegenerative disorders. We employ a cross-disciplinary systems biology-based approach that encompasses genetics, proteomics, microscopy and bioinformatics in yeast, mouse and human/patient cells to identify the proteins that constitute DDR pathways, and study their impact on genome stability maintenance and human disease.

Our research focuses on the following topics:

1.  Systems analysis of the DNA damage response

To dissect the DDR, we use Epistatic MiniArray Profiling (EMAP) to map gene-gene interactions within the complex DRR network. In addition, we use genetic and proteomic screens to identify and characterize genes and pathways involved in the DDR network. An integrated bioinformatics approach is used to analyze cellular pathways and visualize DDR networks.

2.   Chromatin-modifying factors in DNA repair and human disease

Efficient detection and repair of DNA damage is complicated by the fact that genomic DNA is packaged into chromatin. Chromatin-modifying enzymes may help to overcome this barrier at sites of DNA damage. We are systematically identifying and characterizing the chromatin-modifying enzymes that operate during DNA repair and are studying how these enzymes prevent human diseases. 

3.  Ubiquitinating and de-ubiquitinating enzymes in DNA repair and cancer

Post-translational modifications of proteins play essential roles in the regulation of the DDR. Ubiquitination is one the key modifications in the DDR, yet its functions are often poorly understood. We have identified several ubiquitinating and deubiquitinating enzymes and are examining their role in DNA repair and potential as drugable targets for anticancer therapy.  

4.  Functional analysis of genetic variants in putative breast cancer susceptibility genes 

Missense variants in putative breast cancer susceptibility genes are routinely detected in patients with a family history of breast cancer, yet it is often difficult to predict a direct correlation with cancer predisposition. Many of the putative breast cancer susceptibility genes have functions in DNA repair. We are developing repair-based assays to measure the functional consequences of missense mutations in these genes, aiming at a better prediction for cancer predisposition.