Mechanistic Biology of FAN1

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The ability to hydrolyse DNA in a structure specific manner isessential to life and yet presents a formidable molecular recognition challenge.FANCD2/FANCI-associated nuclease (FAN1) is an example of a vital structurespecificnuclease that is involved in repair of interstrand cross-links in DNA. Theassociation of its mutations with several cancers and degenerative diseasesillustrates the importance of FAN1. FAN1 hydrolyses 5' flap structures and bluntends cutting 3 nucleotides into a duplex, but has a completely different structureto other 5' nucleases not involved in cross-link repair. Two crystallographicstructures of the FAN1-DNA complexes have been reported. However, thesediffer considerably e.g., in binding mode to DNA (bent or straight), number ofprotein molecules bound to one DNA etc. and consequently two very differentmodels for FAN1 action have been proposed. Here we plan to investigate themechanistic biology of FAN1 action resolving this debate.