{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T09:24:07Z","timestamp":1787649847567,"version":"build-2736575974"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004376","name":"Terry Fox Research Institute","doi-asserted-by":"publisher","award":["TFRI 1082"],"award-info":[{"award-number":["TFRI 1082"]}],"id":[{"id":"10.13039\/501100004376","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004376","name":"Terry Fox Research Institute","doi-asserted-by":"publisher","award":["TFRI 1155"],"award-info":[{"award-number":["TFRI 1155"]}],"id":[{"id":"10.13039\/501100004376","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004376","name":"Terry Fox Research Institute","doi-asserted-by":"publisher","award":["FDN-148429"],"award-info":[{"award-number":["FDN-148429"]}],"id":[{"id":"10.13039\/501100004376","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004376","name":"Terry Fox Research Institute","doi-asserted-by":"publisher","award":["495630"],"award-info":[{"award-number":["495630"]}],"id":[{"id":"10.13039\/501100004376","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001006","name":"Breast Cancer Research Foundation","doi-asserted-by":"publisher","award":["BCRF-25-180"],"award-info":[{"award-number":["BCRF-25-180"]}],"id":[{"id":"10.13039\/100001006","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001006","name":"Breast Cancer Research Foundation","doi-asserted-by":"publisher","award":["BCRF-26-180"],"award-info":[{"award-number":["BCRF-26-180"]}],"id":[{"id":"10.13039\/100001006","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CDMRP Breast Program","award":["HT94252310820"],"award-info":[{"award-number":["HT94252310820"]}]},{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001804","name":"Canada Research Chairs Program","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001804","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Canadian Cancer Research Society"},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Drug-related UVA-induced photoreactions have been reported for several therapeutic compounds, including fluoroquinolones. CX-5461 is a clinical stage quinolone-derived anti-cancer small molecule with documented UVA-sensitizing activity. Here, we compared, by bulk and clonal whole-genome sequencing under extraneous light-protected conditions, the mutational signatures in human retinal pigment epithelial cells (RPE1) exposed to UVA, CX-5461, or co-exposed to UVA and CX-5461. Treatment with CX-5461 or UVA alone resulted in a low single-base mutation burden and background-like mutational profiles. In contrast, bulk sequencing of human cells co-exposed to UVA and CX-5461 had a markedly higher mutation burden characterized by T &amp;gt; A and T &amp;gt; C substitutions. Furthermore, single-cell clonal expansion and sequencing of CX-5461 alone, UVA alone, or CX-5461+UVA treatments confirmed that the pattern was only observed when cells were exposed to both UVA and CX-5461. The CX-5461+UVA-associated SBS signature we report arises only when CX-5461-treated cells are exposed to UVA, and is not observed when CX-5461-treated cells are shielded from light. We do not observe strong single-base mutagenic activity of CX-5461 alone, under light-protected conditions. Our data define a human SBS mutagenesis signature for CX-5461 potentiated UVA mutations and emphasize the need for appropriate controls and light-exposure precautions when studying SBS activity of known photosensitizer molecules.<\/jats:p>","DOI":"10.1093\/nar\/gkag836","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T11:17:17Z","timestamp":1786706237000},"source":"Crossref","is-referenced-by-count":0,"title":["The UVA-induced single-base mutational signature of CX-5461 in human cells"],"prefix":"10.1093","volume":"54","author":[{"given":"Elena","family":"Zaikova","sequence":"first","affiliation":[{"name":"BC Cancer Research Institute , 675 W10th Avenue, Vancouver, British Columbia, V5Z 1L3 ,","place":["Canada"]},{"name":"Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5370-4592","authenticated-orcid":false,"given":"Damian","family":"Yap","sequence":"additional","affiliation":[{"name":"BC Cancer Research Institute , 675 W10th Avenue, Vancouver, British Columbia, V5Z 1L3 ,","place":["Canada"]},{"name":"Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armaghan","family":"Sarvar","sequence":"additional","affiliation":[{"name":"BC Cancer Research Institute , 675 W10th Avenue, Vancouver, British Columbia, V5Z 1L3 ,","place":["Canada"]},{"name":"Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Auden","family":"Hafezi","sequence":"additional","affiliation":[{"name":"BC Cancer Research Institute , 675 W10th Avenue, Vancouver, British Columbia, V5Z 1L3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Tan","sequence":"additional","affiliation":[{"name":"BC Cancer Research Institute , 675 W10th Avenue, Vancouver, British Columbia, V5Z 1L3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Cerda","sequence":"additional","affiliation":[{"name":"BC Cancer Research Institute , 675 W10th Avenue, Vancouver, British Columbia, V5Z 1L3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaylee","family":"Li","sequence":"additional","affiliation":[{"name":"BC Cancer Research Institute , 675 W10th Avenue, Vancouver, British Columbia, V5Z 1L3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Lai","sequence":"additional","affiliation":[{"name":"BC Cancer Research Institute , 675 W10th Avenue, Vancouver, British Columbia, V5Z 1L3 ,","place":["Canada"]},{"name":"Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4111-2757","authenticated-orcid":false,"given":"Karen","family":"Gelmon","sequence":"additional","affiliation":[{"name":"Medical Oncology, BC Cancer Agency , 600 W10th Avenue, Vancouver, British Columbia, V5Z 1L3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hilton","sequence":"additional","affiliation":[{"name":"Ottawa Hospital Cancer Centre, 501 Smyth Rd, Ottawa , Ontario, K1H 8L1 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8081-0799","authenticated-orcid":false,"given":"Lesley","family":"Seymour","sequence":"additional","affiliation":[{"name":"Canadian Cancer Trials Group , 10 Stuart Street, Kingston, Ontario, K7L 3N6 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2651-4539","authenticated-orcid":false,"given":"Peter","family":"Stirling","sequence":"additional","affiliation":[{"name":"BC Cancer Research Institute , 675 W10th Avenue, Vancouver, British Columbia, V5Z 1L3 ,","place":["Canada"]},{"name":"Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W","family":"Cescon","sequence":"additional","affiliation":[{"name":"Medical Oncology, Princess Margaret Hospital, 610 University Ave , Toronto, Ontario, M5G 2C4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Aparicio","sequence":"additional","affiliation":[{"name":"BC Cancer Research Institute , 675 W10th Avenue, Vancouver, British Columbia, V5Z 1L3 ,","place":["Canada"]},{"name":"Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z4 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"2026082505094391400_B1","doi-asserted-by":"publisher","first-page":"14432","DOI":"10.1038\/ncomms14432","article-title":"CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1\/2 deficient tumours","volume":"8","author":"Xu","year":"2017","journal-title":"Nat Commun"},{"key":"2026082505094391400_B2","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1158\/2159-8290.CD-18-1455","article-title":"First-in-human RNA polymerase I transcription inhibitor CX-5461 in patients with advanced hematologic cancers: results of a phase I dose-escalation study","volume":"9","author":"Khot","year":"2019","journal-title":"Cancer Discov"},{"key":"2026082505094391400_B3","doi-asserted-by":"publisher","first-page":"3607","DOI":"10.1038\/s41467-022-31199-2","article-title":"Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies","volume":"13","author":"Hilton","year":"2022","journal-title":"Nat Commun"},{"key":"2026082505094391400_B4","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1046\/j.1523-1747.2003.12422.x","article-title":"Molecular responses to photogenotoxic stress induced by the antibiotic lomefloxacin in human skin cells: from DNA damage to apoptosis","volume":"121","author":"Marrot","year":"2003","journal-title":"J Invest Dermatol"},{"key":"2026082505094391400_B5","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1039\/b209220b","article-title":"Photophysics and photochemistry of fluoroquinolones","volume":"32","author":"Albini","year":"2003","journal-title":"Chem Soc Rev"},{"key":"2026082505094391400_B6","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.1016\/j.cell.2015.11.015","article-title":"High-resolution CRISPR screens reveal fitness genes and genotype-specific cancer liabilities","volume":"163","author":"Hart","year":"2015","journal-title":"Cell"},{"key":"2026082505094391400_B7","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/s41586-018-0291-z","article-title":"CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions","volume":"559","author":"Zimmermann","year":"2018","journal-title":"Nature"},{"key":"2026082505094391400_B8","doi-asserted-by":"publisher","article-title":"Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM","author":"Li","DOI":"10.48550\/arXiv.1303.3997"},{"key":"2026082505094391400_B9","article-title":"Genomics analysis with Spark, Docker and clouds O\u2019Reilly Media","author":"O\u2019Connor","year":"2020"},{"key":"2026082505094391400_B10","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1038\/ng.806","article-title":"A framework for variation discovery and genotyping using next-generation DNA sequencing data","volume":"43","author":"DePristo","year":"2011","journal-title":"Nat Genet"},{"key":"2026082505094391400_B11","doi-asserted-by":"publisher","article-title":"Calling somatic SNVs and indels with Mutect2","author":"Benjamin","DOI":"10.1101\/861054"},{"key":"2026082505094391400_B12","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/s41588-023-01602-9","article-title":"The chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cells","volume":"56","author":"Koh","year":"2024","journal-title":"Nat Genet"},{"key":"2026082505094391400_B13","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1186\/s12864-019-6041-2","article-title":"SigProfilerMatrixGenerator: a tool for visualizing and exploring patterns of small mutational events","volume":"20","author":"Bergstrom","year":"2019","journal-title":"BMC Genomics"},{"key":"2026082505094391400_B14","doi-asserted-by":"publisher","first-page":"100179","DOI":"10.1016\/j.xgen.2022.100179","article-title":"Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor","volume":"2","author":"Ashiqul\u00a0Islam","year":"2022","journal-title":"Cell Genom"},{"key":"2026082505094391400_B15","doi-asserted-by":"publisher","first-page":"1892","DOI":"10.1038\/s41588-023-01545-1","article-title":"Effects of psoriasis and psoralen exposure on the somatic mutation landscape of the skin","volume":"55","author":"Olafsson","year":"2023","journal-title":"Nat Genet"},{"key":"2026082505094391400_B16","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1186\/s12864-022-08357-3","article-title":"MutationalPatterns: the one stop shop for the analysis of mutational processes","volume":"23","author":"Manders","year":"2022","journal-title":"BMC Genomics"},{"key":"2026082505094391400_B17","article-title":"ggplot2: elegant Graphics for Data Analysis Springer","author":"Wickham","year":"2016"},{"key":"2026082505094391400_B18","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1534\/genetics.120.303169","article-title":"A multimodal genotoxic anticancer drug characterized by pharmacogenetic analysis in Caenorhabditis elegans","volume":"215","author":"Ye","year":"2020","journal-title":"Genetics"},{"key":"2026082505094391400_B19","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1038\/s41586-020-1943-3","article-title":"The repertoire of mutational signatures in human cancer","volume":"578","author":"Alexandrov","year":"2020","journal-title":"Nature"},{"key":"2026082505094391400_B20","doi-asserted-by":"publisher","first-page":"1402","DOI":"10.1038\/ng.3441","article-title":"Clock-like mutational processes in human somatic cells","volume":"47","author":"Alexandrov","year":"2015","journal-title":"Nat Genet"},{"key":"2026082505094391400_B21","first-page":"671","article-title":"Dosimetry of solar ultraviolet radiation. Daily and monthly changes in Paris","volume":"114","author":"Jeanmougin","year":"1987","journal-title":"Ann Dermatol Venereol"},{"key":"2026082505094391400_B22","doi-asserted-by":"publisher","article-title":"Reply to: the chemotherapeutic drug CX-5461 is a potent mutagen in cultured human cells","author":"Kanwal","DOI":"10.1101\/2025.09.30.25336525"},{"key":"2026082505094391400_B23","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1021\/ml300110s","article-title":"Discovery of CX-5461, the first direct and selective inhibitor of RNA polymerase I, for cancer therapeutics","volume":"3","author":"Haddach","year":"2012","journal-title":"ACS Med Chem Lett"},{"key":"2026082505094391400_B24","doi-asserted-by":"publisher","first-page":"9812","DOI":"10.1038\/s41598-021-88988-w","article-title":"Ubiquitin-mediated DNA damage response is synthetic lethal with G-quadruplex stabilizer CX-5461","volume":"11","author":"Masud","year":"2021","journal-title":"Sci Rep"},{"key":"2026082505094391400_B25","doi-asserted-by":"publisher","first-page":"e65184","DOI":"10.7554\/eLife.65184","article-title":"Transcription-associated topoisomerase 2\u03b1 (TOP2A) activity is a major effector of cytotoxicity induced by G-quadruplex ligands","volume":"10","author":"Bossaert","year":"2021","journal-title":"eLife"},{"key":"2026082505094391400_B26","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1016\/j.cell.2020.05.040","article-title":"A genetic map of the response to DNA damage in human cells","volume":"182","author":"Olivieri","year":"2020","journal-title":"Cell"}],"container-title":["Nucleic Acids Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/54\/16\/gkag836\/70775842\/gkag836.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/54\/16\/gkag836\/70775842\/gkag836.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T09:09:50Z","timestamp":1787648990000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nar\/article\/doi\/10.1093\/nar\/gkag836\/8769953"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,24]]},"references-count":26,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2026,8,24]]}},"URL":"https:\/\/doi.org\/10.1093\/nar\/gkag836","relation":{},"ISSN":["0305-1048","1362-4962"],"issn-type":[{"value":"0305-1048","type":"print"},{"value":"1362-4962","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,9,9]]},"published":{"date-parts":[[2026,8,24]]},"article-number":"gkag836"}}