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Research Themes

Research lines

The Department of Molecular Genetics focusses on the DNA damage response through three major integrated lines of research:

(1) Mechanisms of the DNA damage response
(2) The impact and application of the DNA damage response in cancer
(3) The impact and application of the DNA damage response in aging

(1) Mechanisms of the DNA damage response – multidisciplinary research


ExpertiseThis research line addresses the fundamental mechanistic aspects and diurnal organization of the DNA damage response by pursuing complementary and interwoven approaches at both the molecular and cellular level. The molecular mechanisms of the multiple pathways of the DNA damage response are studied by applying and developing (single molecule) biochemical analyses, advanced proteomic analyses and state-of-the-art molecular imaging techniques to identify dynamic molecular interactions that are responsible for the assembly and disassembly of the molecular factories that guard and repair the genome. At the cellular level the DNA damage repair processes in (live) cells are monitored in real time for how they detect DNA damage and proceed to assemble and disassemble the repair machinery by applying the latest super-resolution techniques to understand the interplay between different DNA damage response pathways and their integration in the physiology of the cell.

The ultimate goal should be to define and dissect the molecular circuits of DNA damage repair and their integration in cellular processes. This knowledge is pivotal for identifying molecular targets for designing novel mechanism-based interventions and manipulations of these processes. This will provide the basis for improving existing approaches and developing entirely novel and innovative precision therapies for cancer and aging-related diseases.

More information can be found at:

- Kanaar Lab
- Lans Lab
- Lebbink Lab
- Marteijn Lab
- Nonnekens Lab
- Pothof Lab
- Ray Chaudhuri Lab
- van Gent Lab
- Vermeulen Lab
- Wyman Lab

(2) The impact and application of the DNA damage response in cancer – link with the clinic

Many important anti-cancer treatments are based on the cell killing properties of DNA-damaging agents. The efficacy of such treatments depends on characteristics of the DNA damage response in tumor cells, and depending on the pathways involved, can be subject to circadian variation. The DNA damage response is almost invariably compromised in tumors and can be exploited to develop better patient selection methods, to guide targeted cancer treatments and to design novel precision cancer treatments, including protocols in which anti-cancer drugs are administered at the time of the day when tumor cells are most sensitive and/or healthy cells are best protected (chronotherapy).

Custom-made genetically engineered pre-clinical mouse models and orthotopic tumor mouse models are and should be further developed and used to test treatments that are rationally designed based on molecular mechanistic insights from the ‘Mechanisms of the DNA damage response’ research line. This will involve unique Erasmus MC resources for 3D imaging to identify and locate molecular processes in action in vivo in live mice in a longitudinal manner. The ultimate goal, in combination with the ex vivo functional assays on patient-derived materials described below, should be to develop (biology-based) image-guided, adaptive and targeted cancer therapies.  

Based on extensive analysis of the DNA damage response in cell culture the Department has developed a clinic-to-lab pipeline for breast cancer patients that allows testing, in a functional ex vivo assay, aspects of the DNA damage response in viable (organotypic) slices of tumor material from individual patients. In the case of breast cancer these assays allows selection of patients for a specific targeted therapy. This method is now poised to move from the lab back to the clinic through a clinical trial in collaboration with the Erasmus MC Department of Medical Oncology. The responses observed in the ex vivo DNA damage response on biopsies from individual breast cancer patients will be correlated with outcome of their clinical treatment.

A major goal within this research line should be to obtain a direct functional appraisal of the DNA damage response capacity for individual patient tumors. Based on this principle, functional assays will be developed for multiple DNA damage response reactions and extend beyond breast cancer to other tumor sites. These assays will ultimately identify specific defects in DNA damage response that can be exploited in the exciting new strategy of synthetic lethality approaches, as pioneered for hereditary breast and ovarian cancer. The potential for synthetic lethality is in principle general and needs to be systematically explored in general for other tumors.

 Molecular circuits of DNA damage repair


More information can be found at:

- Chien Lab
- Essers Lab
- Hoeijmakers Lab
- Kanaar Lab
- Lans Lab
- Nonnekens Lab
- Pothof Lab
- Ray Chaudhuri Lab
- van der Horst Lab
- van Gent Lab

(3) The impact and application of the DNA damage response in aging - towards intervention strategies for diseases associated with aging-related symptoms


Research Genetics IntroThe problem of DNA damage not only fosters mutagenesis and thereby carcinogenesis, it also constitutes a major cause of cellular dysfunction, cell death and cellular senescence, driving the process of aging. As a consequence many inborn disorders due to genetic deficiencies in DNA damage response pathways exhibit a strong cancer predisposition and/or premature aging symptoms. The Department has invested in generating a comprehensive series of mouse mutants carrying engineered defects in specific repair genes, some of which precisely mimic the defect of a DNA repair deficient patient. These mouse mutants turned out to be extremely informative as they not only mimicked the corresponding human syndromes to an exceptional degree but also enabled detailed insight into the complex etiology of human repair syndromes. In this way a strong connection between accumulating DNA damage and accelerated but truly bona fide aging was discovered as trade-off between cancer and aging. This collection of genetically engineered progeroid mouse mutants, which is unique in the world, provides the Department with an exclusive competitive advantage and should be explored for the development of intervention strategies for diseases associated with aging-related symptoms.

More information can be found at:

-Essers Lab
-Hoeijmakers Lab
-Mastroberardino Lab
-Pothof Lab
-van der Horst Lab