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Previous study has identified that missense mutation or loss of the NER genes Excision Repair Cross Complementation Group 1 and 2 (ERCC1 and ERCC2) leads to improved patient outcomes after treatment with Pt-based chemotherapies. Although most NER gene alterations found in patient tumors are missense mutations, the impact of mutations in the remaining nearly 20 NER genes is unknown. Towards this goal, we previously developed a machine learning strategy to predict genetic variants in an essential NER protein, Xeroderma Pigmentosum Complementation Group A (XPA), that disrupt repair. In this study, we report in-depth analyses of a subset of the predicted variants, including in vitro analyses of purified recombinant protein and cell-based assays to test Pt agent sensitivity in cells and determine mechanisms of NER dysfunction. The most NER deficient variant Y148D had reduced protein stability, weaker DNA binding, disrupted recruitment to damage, and degradation. Our findings demonstrate that tumor mutations in XPA impact cell survival after cisplatin treatment and provide valuable mechanistic insights to improve variant effect prediction. Broadly, these findings suggest XPA tumor variants should be considered when predicting chemotherapy response.<\/jats:p>","DOI":"10.1093\/narcan\/zcae013","type":"journal-article","created":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T10:45:57Z","timestamp":1709203557000},"source":"Crossref","is-referenced-by-count":8,"title":["XPA tumor variant leads to defects in NER that sensitize cells to cisplatin"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4959-5466","authenticated-orcid":false,"given":"Alexandra M","family":"Blee","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University , Nashville , TN\u00a0 37205 , USA"},{"name":"Center for Structural Biology, Vanderbilt University , Nashville , TN\u00a0 37240 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlyn\u00a0S","family":"Gallagher","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University , Nashville , TN\u00a0 37205 , USA"},{"name":"Center for Structural Biology, Vanderbilt University , Nashville , TN\u00a0 37240 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun-Suk","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Genomic Integrity, Institute for Basic Science , Ulsan\u00a0 44919 , Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Genomic Integrity, Institute for Basic Science , Ulsan\u00a0 44919 , Republic of Korea"},{"name":"Department of Biological Sciences, Ulsan National Institute of Science and Technology , Ulsan\u00a0 44919 , Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suhas\u00a0S","family":"Kharat","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University , Nashville , TN\u00a0 37205 , USA"},{"name":"Center for Structural Biology, Vanderbilt University , Nashville , TN\u00a0 37240 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina\u00a0R","family":"Troll","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Vanderbilt University , Nashville , TN\u00a0 37240 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Areetha","family":"D\u2019Souza","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University , Nashville , TN\u00a0 37205 , USA"},{"name":"Center for Structural Biology, Vanderbilt University , Nashville , TN\u00a0 37240 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyoung","family":"Park","sequence":"additional","affiliation":[{"name":"Center for Genomic Integrity, Institute for Basic Science , Ulsan\u00a0 44919 , Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00a0Drew","family":"Neufer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University , Nashville , TN\u00a0 37205 , USA"},{"name":"Center for Structural Biology, Vanderbilt University , Nashville , TN\u00a0 37240 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orlando\u00a0D","family":"Sch\u00e4rer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University , Nashville , TN\u00a0 37205 , USA"},{"name":"Center for Genomic Integrity, Institute for Basic Science , Ulsan\u00a0 44919 , Republic of Korea"},{"name":"Department of Biological Sciences, Ulsan National Institute of Science and Technology , Ulsan\u00a0 44919 , Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter\u00a0J","family":"Chazin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University , Nashville , TN\u00a0 37205 , USA"},{"name":"Center for Structural Biology, Vanderbilt University , Nashville , TN\u00a0 37240 , USA"},{"name":"Department of Chemistry, Vanderbilt University , Nashville , TN\u00a0 37240 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,3,18]]},"reference":[{"key":"2024040216221383400_B1","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1021\/cr040483f","article-title":"Molecular mechanisms of mammalian global genome nucleotide excision repair","volume":"106","author":"Gillet","year":"2006","journal-title":"Chem. 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