Research objectives

Genome stability and dynamics

Our primary research interest is how organisms, cells or genomes maintain genetic integrity, and over the last few years we have used the model organism C. elegans to identify and characterize genes whose loss of function results in an enhanced level of spontaneous mutagenesis.   In parallel to cloning these genes via conventional genetic approaches (Tijsterman et al., Science 2002) we have developed sensitive in vivo assays to detect specific types of genomic instability in the nematode, such as micro-satellite instability (Pothof et al., Genes Dev. 2003), G4 DNA instability (Kruisselbrink et al., Curr. Biol. 2008; see also Editors' choice Science 2008 320:1396), DNA transposition and single base-pair substitutions. We have also developed reporter-based single worm assays that allow us to monitor error prone repair of DNA double strand breaks in the context of a developing animal. The rationale has been to create tools that could optimally benefit from the strength of the C. elegans system, a "fast genetic" animal system that has become amenable to systematic genome-wide reverse genetic approaches since the discovery of RNAi.
 
We have progressively worked towards more efficient and faster RNAi screening methods also with the aim to perform synthetic lethal screens in an animal system. Two genes are called synthetic lethal when cell death is manifested if both genes are inactivated, whereas inactivation of only one gene does not lead to loss of viability. Such interactions can have great clinical potential in cases where genes are causally linked to tumorigenesis. To obtain proof of principle for our experimental setup, we used synthetic lethal screening to identify genes that protect the genome from DNA double strand breaks generated by transposon excision (van Haaften et al., PNAS 2004b). The protocol to perform genome-wide RNAi screens in a 96-well liquid platform was also used to directly identify modifiers of the DNA double strand break response (van Haaften et al., Curr. Biol. 2006).
The most promising genes identified in these screens are being studied in further detail using genetic and molecular approaches.
Work in the lab is sponsored by: the Hubrecht Institute, NWO (VIDI grant), the Netherlands Genomics Initiative (NGI-Horizon grant), the Dutch Cancer Society (KWF), the European Research Counsel (ERC-Starting grant) and the Cancer Genomics Centre (CGC).

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