{"doi":"10.1093/nar/gkae1290","title":"Evidence for intrinsic DNA dynamics and deformability in damage sensing by the Rad4/XPC nucleotide excision repair complex","abstract":"Altered DNA dynamics at lesion sites are implicated in how DNA repair proteins sense damage within genomic DNA. Using laser temperature-jump (T-jump) spectroscopy combined with cytosine-analog Förster Resonance Energy Transfer (FRET) probes that sense local DNA conformations, we measured the intrinsic dynamics of DNA containing 3 base-pair mismatches recognized in vitro by Rad4 (yeast ortholog of XPC). Rad4/XPC recognizes diverse lesions from environmental mutagens and initiates nucleotide excision repair. T-jump measurements, together with a novel and rigorous comparison with equilibrium FRET, uncovered conformational dynamics spanning multiple timescales and revealed key differences between Rad4-specific and non-specific DNA. AT-rich non-specific sites (matched or mismatched) exhibited dynamics primarily within the T-jump observation window, albeit with some amplitude in 'missing' fast (<20 μs) kinetics. These fast-kinetics amplitudes were dramatically larger for specific sites (CCC/CCC and TTT/TTT), which also exhibited 'missing' slow (>50 ms) kinetics at elevated temperatures, unseen in non-specific sites. We posit that the rapid (μs-ms) intrinsic DNA fluctuations help stall a diffusing protein at AT-rich/damaged sites and that the >50-ms kinetics in specific DNA reflect a propensity to adopt unwound/bent conformations resembling Rad4-bound DNA structures. These studies provide compelling evidence for sequence/structure-dependent intrinsic DNA dynamics and deformability that likely govern damage sensing by Rad4.","journal":"Nucleic Acids Research","year":2024,"id":460675,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":414271,"name":"Sagnik Chakraborty","orcid":"0000-0003-3072-5056","position":1,"is_corresponding":false},{"id":364785,"name":"Peter Steinbach","orcid":"0000-0002-6710-3472","position":2,"is_corresponding":false},{"id":414268,"name":"Debamita Paul","orcid":"0000-0003-4535-9642","position":3,"is_corresponding":false},{"id":414273,"name":"Jung‐Hyun Min","orcid":"0000-0002-4221-9321","position":4,"is_corresponding":false},{"id":415073,"name":"Anjum Ansari","orcid":null,"position":5,"is_corresponding":false},{"id":585074,"name":"Saroj Baral","orcid":null,"position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:04:07.925246Z","pmid":"39797732","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":[]}