John Rouse Wins 2017 Fanconi Anemia Research Fund Discovery Award

John Rouse, together with researchers Detlev Schindler at the University of Wuerzburg, and Minoru Takata at the University of Kyoto, have won the Fanconi Anemia Research Fund 2017 Discovery Award for the discovery and characterization of the Fanconi anemia gene FANCW.

Commenting on the award John said: “I’m delighted that our work on FANCW should be recognized by the Fanconi Anemia Research Fund. The efforts in my lab are the result of the fantastic talents and hard work of Laura Feeney, a PhD student who was part of my team before she started postdoctoral research at the Memorial Sloan Kettering Cancer Center NYC. The project also had important input from two talented postdoctoral researchers - Ivan Muñoz and Christophe Lachaud.”

Laura, Ivan and Christophe found that FANCW, an E3 ubiquitin ligase also known as RFWD3, is critical for repair of a dangerous type of DNA damage known as inter-strand crosslinks (ICLs); failure to repair ICLs is associated with Fanconi anemia (FA). The last step in the repair of ICLs involves a process known as homologous recombination (HR).

John’s team showed that during HR, RFWD3 removes the DNA repair protein RPA from DNA damage sites to allow access of the RAD51 recombinase – RPA removal relies on its ubiquitylation by RFWD3. Failure of RPA ubiquitylation in cells defective in RFWD3/FANCW causes a major defect in homologous recombination (HR). John’s team showed that FA-associated RFWD3 mutations abolish its interaction with RPA, and inhibit RPA removal from DNA damage sites which explains why RFWD3 mutations cause FA. These findings pinpoint a new mechanism for controlling DNA repair, keeping our genome stable and preventing human disease.