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Inactivating mutations in XPA cause xeroderma pigmentosum (XP), which is characterized by extreme UV sensitivity and a highly elevated skin cancer risk. Here, we describe two Dutch siblings in their late forties carrying a homozygous H244R substitution in the C-terminus of XPA. They present with mild cutaneous manifestations of XP without skin cancer but suffer from marked neurological features, including cerebellar ataxia. We show that the mutant XPA protein has a severely weakened interaction with the transcription factor IIH (TFIIH) complex leading to an impaired association of the mutant XPA and the downstream endonuclease ERCC1-XPF with NER complexes. Despite these defects, the patient-derived fibroblasts and reconstituted knockout cells carrying the XPA-H244R substitution show intermediate UV sensitivity and considerable levels of residual GG-NER (~50%), in line with the intrinsic properties and activities of the purified protein. By contrast, XPA-H244R cells are exquisitely sensitive to transcription-blocking DNA damage, show no detectable recovery of transcription after UV irradiation, and display a severe deficiency in TC-NER-associated unscheduled DNA synthesis. Our characterization of a new case of XPA deficiency that interferes with TFIIH binding and primarily affects the transcription-coupled subpathway of nucleotide excision repair, provides an explanation of the dominant neurological features in these patients, and reveals a specific role for the C-terminus of XPA in TC-NER.<\/jats:p>","DOI":"10.1073\/pnas.2208860120","type":"journal-article","created":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T14:09:04Z","timestamp":1678370944000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["A disease-associated XPA allele interferes with TFIIH binding and primarily affects transcription-coupled nucleotide excision repair"],"prefix":"10.1073","volume":"120","author":[{"given":"Diana","family":"van den Heuvel","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8347-103X","authenticated-orcid":false,"given":"Mihyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Genomic Integrity, Institute for Basic Science, 44919 Ulsan, Republic of Korea"},{"name":"Department of Biological Sciences, Ulsan National Institute of Science and Technology, 44919 Ulsan, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9959-1917","authenticated-orcid":false,"given":"Annelotte P.","family":"Wondergem","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7616-6689","authenticated-orcid":false,"given":"Paula J.","family":"van der Meer","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myr\u00e8se","family":"Witkamp","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2541-3752","authenticated-orcid":false,"given":"Ferdy","family":"Lambregtse","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun-Suk","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Genomic Integrity, Institute for Basic Science, 44919 Ulsan, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Folkert","family":"Kan","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Apelt","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Kragten","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8997-2321","authenticated-orcid":false,"given":"Rom\u00e1n","family":"Gonz\u00e1lez-Prieto","sequence":"additional","affiliation":[{"name":"Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands"},{"name":"Andalusian Center for Molecular Biology and Regenerative Medicine, University of Sevilla, 41092 Seville, Spain"},{"name":"Department of Cell Biology, University of Seville, 41012 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7989-0493","authenticated-orcid":false,"given":"Alfred C. 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