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Structural basis of cyclobutane pyrimidine dimer recognition by UV-DDB in the nucleosome

Syota Matsumoto, Yoshimasa Takizawa, Mitsuo Ogasawara, Kana Hashimoto, Lumi Negishi, Wenjie Xu, Haruna Tachibana, Junpei Yamamoto, Shigenori Iwai, Kaoru Sugasawa & Hitoshi Kurumizaka

Abstract
In mammalian global genomic nucleotide excision repair, UV-DDB plays a central role in recognizing DNA lesions, such as 6-4 photoproducts and cyclobutane pyrimidine dimers, within chromatin. In the present study, we perform cryo-electron microscopy analyses coupled with chromatin-immunoprecipitation to reveal that the cellular UV-DDB binds to UV-damaged DNA lesions in a chromatin unit, the nucleosome, at a position approximately 20 base-pairs from the nucleosomal dyad in human cells. An alternative analysis of the in vitro reconstituted UV-DDB-cyclobutane pyrimidine dimer nucleosome structure demonstrates that the DDB2 subunit of UV-DDB specifically recognizes the cyclobutane pyrimidine dimer lesion at this position on the nucleosome. We also determine the structures of UV-DDB bound to DNA lesions at other positions in purified cellular human nucleosomes. These cellular and reconstituted UV-DDB-nucleosome complex structures provide important evidence for understanding the mechanism by which UV lesions in chromatin are recognized and repaired in mammalian cells.

Nature Communications, doi: 10.1038/s41467-025-65486-5. (2025)
https://www.nature.com/articles/s41467-025-65486-5