Structural basis of cyclobutane pyrimidine dimer recognition by UV-DDB in the nucleosome
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.
Authors
- Lumi Negishi (ORCID: https://orcid.org/0000-0002-7297-0634)
- Hitoshi Kurumizaka (ORCID: https://orcid.org/0000-0001-7412-3722)
- Yoshimasa Takizawa (ORCID: https://orcid.org/0000-0002-6265-4830)
- H. Tachibana (ORCID: https://orcid.org/0000-0001-5162-1294)
- Kaoru Sugasawa (ORCID: https://orcid.org/0000-0001-7937-4053)
- Junpei Yamamoto (ORCID: https://orcid.org/0000-0002-5036-991X)
- S. Matsumoto (ORCID: https://orcid.org/0000-0002-8776-2096)
- Shigenori Iwai (ORCID: https://orcid.org/0000-0002-7873-937X)
- Wenjie Xu (ORCID: https://orcid.org/0000-0001-8718-3230)
- Mitsuo Ogasawara (ORCID: https://orcid.org/0000-0003-3248-2270)
- Kana Hashimoto
Institutions
- Quantitative BioSciences (US)
- RIKEN Center for Biosystems Dynamics Research (JP)
- Kobe University (JP)
- The University of Tokyo (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-11
- DOI
- https://doi.org/10.1038/s41467-025-65486-5
- Citations
- 1
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Novartis Foundation
- Sumitomo Foundation
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science
- Core Research for Evolutional Science and Technology
- Precursory Research for Embryonic Science and Technology
- Exploratory Research for Advanced Technology