Mutations in the nucleotide excision repair (NER) pathway can cause the 
xeroderma pigmentosum skin cancer predisposition syndrome. NER lesions are 
limited to one DNA strand, but otherwise they are chemically and structurally 
diverse, being caused by a wide variety of genotoxic chemicals and ultraviolet 
radiation. The xeroderma pigmentosum C (XPC) protein has a central role in 
initiating global-genome NER by recognizing the lesion and recruiting downstream 
factors. Here we present the crystal structure of the yeast XPC orthologue Rad4 
bound to DNA containing a cyclobutane pyrimidine dimer (CPD) lesion. The 
structure shows that Rad4 inserts a beta-hairpin through the DNA duplex, causing 
the two damaged base pairs to flip out of the double helix. The expelled 
nucleotides of the undamaged strand are recognized by Rad4, whereas the two 
CPD-linked nucleotides become disordered. These findings indicate that the 
lesions recognized by Rad4/XPC thermodynamically destabilize the Watson-Crick 
double helix in a manner that facilitates the flipping-out of two base pairs.