Mechanistic Biology of FAN1

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