Knipscheer: Genome Maintenance

DNA interstrand crosslink repair

DNA interstrand crosslinks (ICLs) are highly toxic DNA lesions that can form endogenously but are also induced at high doses in cancer chemotherapy. Repair of these lesions is complex and requires the collaboration of proteins from various DNA repair pathways including the Fanconi anemia (FA) pathway. FA is a genetic cancer-predisposition disorder caused by mutation in any of the 21 currently known FA genes. Cells from FA patients are sensitive to ICLs and we and others have shown that the FA pathway directly acts in ICL repair. We have recently shown that the FA pathway plays a pivotal role in a specific step in the repair process, the unhooking of the ICL from one of the DNA strands. These incisions require the activation of the FA pathway by ubiquitinylation of the FANCI-FANCD2 complex, the mediator protein FANCP/SLX4, and the endonuclease FANCQ/XPF-ERCC1 (Knipscheer et al., Science 2009, Klein Douwel, Boonen et al., Mol Cell 2014, Klein Douwel et al., EMBO J 2017). We are currently studying the molecular details of the incisions step and other aspects of ICL repair.