Twist-open mechanism of DNA damage recognition by the Rad4/XPC nucleotide excision repair complex

Significance Impairment of global genome nucleotide excision repair (NER) leads to extreme sun sensitivity and predisposition to cancers. The xeroderma pigmentosum C (XPC) complex senses diverse environmentally induced DNA lesions from predominantly normal DNA, and initiates NER by recruiting downstream factors. Using unique fluorescent approaches, this study unveils previously unresolved DNA dynamics during lesion recognition by radiation-sensitive 4 (Rad4; yeast XPC ortholog) and demonstrates that Rad4 nonspecifically deforms (“twists”) the DNA before specifically recognizing (“opening”) target lesions. These results mark the first observation, to our knowledge, of DNA distortional dynamics that reflect a nonspecific search/interrogation process by a DNA repair protein that relies entirely on DNA deformability to recognize its lesions, and provides keys to understanding the protein’s ability to search rapidly and yet also reliably recognize diverse lesions.