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Knipscheer group

Molecular mechanism and regulation of DNA repair

DNA repair mechanisms are crucial to maintain genomic integrity and prevent cancer. A particularly harmful type of DNA damage is an interstrand crosslink (ICL), which covalently links the two strands of the DNA. High doses of ICLs are used in cancer therapy but ICLs are also formed under normal conditions. Surprisingly little is known about the biochemical mechanism of ICL repair and especially the role of the Fanconi anemia pathway has remained enigmatic. Fanconi anemia is a genetic cancer predisposition disorder characterized by hypersensitivity to ICLs. We use Xenopus laevis egg extracts to recapitulate ICL repair in vitro, which allows us to study its molecular mechanism and regulation.

Fast Facts: A roadblock on the DNA highway from Fast Facts on Vimeo.

Key publications
Knipscheer, P., Räschle, M., Smogorzewska, A., Enoiu, M., Ho, T.V., Schärer, O.D., Elledge, S.J., Walter, J.C. (2009) The Fanconi anemia pathway promotes replication-dependent DNA interstrand crosslink repair. Science 326: 1698-1701.

Räschle, M., Knipscheer, P., Enoiu, M., Angelov, T., Sun, J., Griffith, J.D., Ellenberger, T.E., Schärer, O.D., Walter, J.C. (2008) Mechanism of Replication-Coupled DNA Interstrand Crosslink Repair. Cell134: 969-980.

Knipscheer*, P., Flotho*, A., Klug*, H., Olsen, J.V., van Dijk, W.J., Fish, A., Johnson, E.S., Mann, M., Sixma, T.K., Pichler A. (2008) Ubc9 sumoylation regulates SUMO target discrimination. Mol. Cell 31: 371-382.

Knipscheer, P., van Dijk, W.J., Olsen, J.V., Mann, M., Sixma, T.K. (2007) Non-covalent interaction between Ubc9 and SUMO promotes SUMO chain formation. EMBO Journal 26: 2797-2807.

Pichler*, A., Knipscheer*, P., Oberhofer, E., van Dijk, W.J., Korner, R,. Olsen, J.V., Jentsch, S., Melchior, F., Sixma, T.K. (2005) SUMO modification of the ubiquitin-conjugating enzyme E2-25K. Nat. Struct. Mol. Biol. 12: 264-269.