Title

How does the Fanconi pathway promote unhooking of DNA interstrand crosslinks?

Speaker:

Dr Puck Knipscheer, Hubrecht Institute, Utrecht, Netherlands

Date & Time:

Thursday, 24 March 2016, 12:30

Location: 
MRC Weatherall Institute of Molecular Medicine, Seminar Room, Headington OX3 9DS
Host: 
WIMM Occasional Seminars

DNA interstrand cross-links (ICLs) are highly toxic DNA lesions as they prevent DNA strand separation. ICL repair requires several classes of repair enzymes including translesion DNA polymerases, structure-specific endonucleases, recombinases, and Fanconi anemia (FA) proteins. Mutation in any one of the 16 currently known FA genes leads to the cancer predisposition disorder Fanconi anemia. However, it is still largely unclear how the FA proteins and the other repair factors collaborate to repair ICLs.
We study the molecular mechanism of ICL repair using a Xenopus egg extract-based system that recapitulates replication-dependent ICL repair in vitro. Previously we have shown that activation of the FA pathway by ubiquitylation of the FANCI-FANCD2 (ID) complex is important for a specific step in ICL repair, namely the incisions that unhook the lesion from one of the DNA strands. We next demonstrated that binding of this activated ID complex to the crosslink promotes the recruitment of the incision-complex, composed of the adapter protein SLX4 and the structure specific endonuclease XPF-ERCC1. Both XPF and SLX4 have recently been identified as FA genes highlighting their importance in ICL repair. Although ICL unhooking appears to be a major function of the FA pathway the biochemical details of this process are still unclear. I will present our latest findings regarding the role of XPF-ERCC1 and SLX4 in ICL repair.

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