Human Genetics— Chromatin and DNA repair
Human Genetics

Chromatin and DNA repair

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:

  • Systems analysis of the DNA damage response
  • Chromatin-modifying factors in DNA repair and human disease
  • Ubiquitinating and de-ubiquitinating enzymes in DNA repair and cancer
  • Functional analysis of genetic variants in putative breast cancer susceptibility genes

Projects

Systems analysis of the DNA damage response
Chromatin-modifying factors in DNA repair and human disease
Ubiquitinating and de-ubiquitinating enzymes in DNA repair and cancer
Functional analysis of genetic variants in putative breast cancer susceptibility genes

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.

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.

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. 

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.

Key Publications

TRiC controls transcription resumption after UV damage by regulating Cockayne syndrome protein A
A PALB2-interacting domain in RNF168 couples homologous recombination to DNA break-induced chromatin ubiquitylation
Ataxin-3 consolidates the MDC1-dependent DNA double-strand break response by counteracting the SUMO-targeted ubiquitin ligase RNF4
ZMYND8 co-localizes with NuRD on target genes and regulates recruitment of GATAD2A/NuRD to sites of DNA damage
PARP1 Links CHD2-Mediated Chromatin Expansion and H3.3 Deposition to DNA Repair by Non-homologous End-Joining
A UV–induced genetic network links the RSC complex to nucleotide excision repair and displays dose-dependent rewiring
Dissection of DNA damage responses using multi-conditional genetic interaction maps
The yeast Fun30 and human SMARCAD1 chromatin remodellers promote DNA end-resection
Rewiring of genetic networks in response to DNA damage
The NuRD chromatin remodeling complex regulates signaling and repair of DNA damage
All publications

Our Team

Prof.dr. Haico van Attikum         
Principal Investigator / Professor Chromatin and DNA-repair

Rick A.C.M. Boonen                     
Researcher

Bert W. van de Kooij
Researcher

Magdalena B. Krawitowska-Rother         
Researcher

…

Prof.dr. Haico van Attikum         
Principal Investigator / Professor Chromatin and DNA-repair

Rick A.C.M. Boonen                     
Researcher

Bert W. van de Kooij
Researcher

Magdalena B. Krawitowska-Rother         
Researcher

Fenna J. van der Wal     
PhD student

Sophie C. van der Horst
PhD student

Jolanthe Lingeman         
PhD student

Anton J.L. de Groot                       
Research technician

Sabine C. Knaup                             
Research technician

Kees Vreeken                   
Research technician

Wouter W. Wiegant      
Research technician