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Yet, our understanding of the complex NER protein machinery remains incomplete. Combining cryo-EM and XL-MS data with AlphaFold2 predictions, we build an integrative model of the NER pre-incision complex(PInC). Here TFIIH serves as a molecular ruler, defining the DNA bubble size and precisely positioning the XPG and XPF nucleases for incision. Using simulations and graph theoretical analyses, we unveil PInC\u2019s assembly, global motions, and partitioning into dynamic communities. Remarkably, XPG caps XPD\u2019s DNA-binding groove and bridges both junctions of the DNA bubble, suggesting a novel coordination mechanism of PInC\u2019s dual incision. XPA rigging interlaces XPF\/ERCC1 with RPA, XPD, XPB, and 5\u2032 ssDNA, exposing XPA\u2019s crucial role in licensing the XPF\/ERCC1 incision. Mapping disease mutations onto our models reveals clustering into distinct mechanistic classes, elucidating xeroderma pigmentosum and Cockayne syndrome disease etiology.<\/jats:p>","DOI":"10.1038\/s41467-024-52860-y","type":"journal-article","created":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T17:01:59Z","timestamp":1727802119000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Molecular architecture and functional dynamics of the pre-incision complex in nucleotide excision repair"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8503-9435","authenticated-orcid":false,"given":"Jina","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunli","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanmoy","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5752-1700","authenticated-orcid":false,"given":"Lucas","family":"Brewer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4918-4571","authenticated-orcid":false,"given":"Susan E.","family":"Tsutakawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0365-2405","authenticated-orcid":false,"given":"Chi-Lin","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5192-1852","authenticated-orcid":false,"given":"Samir M.","family":"Hamdan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1659-2429","authenticated-orcid":false,"given":"John A.","family":"Tainer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5306-1005","authenticated-orcid":false,"given":"Ivaylo","family":"Ivanov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,1]]},"reference":[{"key":"52860_CR1","doi-asserted-by":"publisher","first-page":"a012609","DOI":"10.1101\/cshperspect.a012609","volume":"5","author":"OD Scharer","year":"2013","unstructured":"Scharer, O. 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