Structure and mechanism of pyrimidine–pyrimidone (6-4) photoproduct recognition by the Rad4/XPC nucleotide excision repair complex

Debamita Paul, Hong Mu, Hong Zhao, Ouathek Ouerfelli, Philip D Jeffrey, Suse Broyde and Jung-Hyun Min

Nucleic Acids Res (2019) 47(12): 6015–6028. doi:10.1093/nar/gkz359

This study combines X-ray crystallographic structure determination with computational molecular dynamics simulations to determine a mechanism by which a DNA substrate containing a 6-4 photoproduct (6-4PP) lesion is recognized by a Rad4-Rad23 complex for its repair. This new structure shows how the 6-4PP is completely flipped out of the DNA double helix by Rad4. The authors then use MD simulations to show how the Rad4 initiates the displacement of 6-4PP by causing DNA untwisting, bending and base flipping. This is not the first structure determined of a Rad4-DNA complex; however, it is the first structure of Rad4 (or any XPC ortholog) bound to a bona fide lesion substrate that is recognizable in its natural DNA sequence context for nucleotide excision repair (NER) and provides structural evidence for mechanism of recognition and action that has been lacking.

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