{"doi":"10.1093/nar/gkaa909","title":"Tethering-facilitated DNA ‘opening’ and complementary roles of β-hairpin motifs in the Rad4/XPC DNA damage sensor protein","abstract":"XPC/Rad4 initiates eukaryotic nucleotide excision repair on structurally diverse helix-destabilizing/distorting DNA lesions by selectively 'opening' these sites while rapidly diffusing along undamaged DNA. Previous structural studies showed that Rad4, when tethered to DNA, could also open undamaged DNA, suggesting a 'kinetic gating' mechanism whereby lesion discrimination relied on efficient opening versus diffusion. However, solution studies in support of such a mechanism were lacking and how 'opening' is brought about remained unclear. Here, we present crystal structures and fluorescence-based conformational analyses on tethered complexes, showing that Rad4 can indeed 'open' undamaged DNA in solution and that such 'opening' can largely occur without one or the other of the β-hairpin motifs in the BHD2 or BHD3 domains. Notably, the Rad4-bound 'open' DNA adopts multiple conformations in solution notwithstanding the DNA's original structure or the β-hairpins. Molecular dynamics simulations reveal compensatory roles of the β-hairpins, which may render robustness in dealing with and opening diverse lesions. Our study showcases how fluorescence-based studies can be used to obtain information complementary to ensemble structural studies. The tethering-facilitated DNA 'opening' of undamaged sites and the dynamic nature of 'open' DNA may shed light on how the protein functions within and beyond nucleotide excision repair in cells.","journal":"Nucleic Acids Research","year":2020,"id":79826,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9496,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":415072,"name":"Hong Mu","orcid":null,"position":1,"is_corresponding":false},{"id":414269,"name":"Amirrasoul Tavakoli","orcid":"0000-0002-7991-9858","position":2,"is_corresponding":false},{"id":233670,"name":"Qing Dai","orcid":"0000-0002-8578-1568","position":3,"is_corresponding":false},{"id":414270,"name":"Xuejing Chen","orcid":"0000-0001-6827-0152","position":4,"is_corresponding":false},{"id":414271,"name":"Sagnik Chakraborty","orcid":"0000-0003-3072-5056","position":5,"is_corresponding":false},{"id":21408,"name":"Chuan He","orcid":"0000-0003-4319-7424","position":6,"is_corresponding":false},{"id":415073,"name":"Anjum Ansari","orcid":null,"position":7,"is_corresponding":false},{"id":414272,"name":"Suse Broyde","orcid":"0000-0002-3802-7511","position":8,"is_corresponding":false},{"id":414273,"name":"Jung‐Hyun Min","orcid":"0000-0002-4221-9321","position":9,"is_corresponding":false},{"id":414268,"name":"Debamita Paul","orcid":"0000-0003-4535-9642","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-18T21:50:57.971597Z","pmid":"33119737","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}