{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T08:45:41Z","timestamp":1792140341428,"version":"4.4.0"},"reference-count":37,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA276058"],"award-info":[{"award-number":["R01CA276058"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["U54CA231649"],"award-info":[{"award-number":["U54CA231649"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["UM1CA294119"],"award-info":[{"award-number":["UM1CA294119"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS133439"],"award-info":[{"award-number":["R01NS133439"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000104","name":"National Aeronautics and Space Administration","doi-asserted-by":"publisher","award":["80NSSC23K1018"],"award-info":[{"award-number":["80NSSC23K1018"]}],"id":[{"id":"10.13039\/100000104","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000015","name":"U.S. Department of Energy","doi-asserted-by":"publisher","award":["DE-SC0025578"],"award-info":[{"award-number":["DE-SC0025578"]}],"id":[{"id":"10.13039\/100000015","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>DNA mismatch repair (MMR) deficiency has been widely utilized in forward genetic screens to identify drug resistance mutations and elucidate the mechanisms of action of cytotoxic small molecules. However, MMR deficiency generates a characteristic mutational signature enriched for C &amp;gt; T transitions that precludes saturation of mutagenesis. We hypothesized that expression of proofreading-deficient DNA polymerase epsilon, as has been observed in patients with biallelic MMR deficiency, would enhance mutagenesis and enable identification of new resistance mutations and cytotoxin mechanisms. Here, we combine auxin-inducible degradation of Msh2 with doxycycline-inducible expression of the proofreading-deficient Pol\u03b5P286R mutant in murine small cell lung cancer (SCLC) cells. Simultaneous MMR deficiency and mutant Pol\u03b5 expression markedly increased the emergence of bortezomib-resistant clones relative to either perturbation alone, and targeted sequencing of Psmb5 in bortezomib-resistant clones identified recurrent mutations previously reported in resistance screens using MMR-deficient cells and chemical mutagenesis. We next applied this platform to investigate resistance to lurbinectedin, a clinically relevant therapy for SCLC. Whole-exome sequencing revealed recurrent loss-of-function alterations in nucleotide excision repair (NER) genes, most notably Ercc5 and Ercc4, implicating NER deficiency as a major mechanism of lurbinectedin resistance and supporting a central role for NER in mediating lurbinectedin-induced cytotoxicity. Collectively, these findings establish inducible ultramutagenesis as a powerful and versatile platform for the unbiased discovery of drug resistance mechanisms and therapeutic vulnerabilities.<\/jats:p>","DOI":"10.1021\/acschembio.6c00605","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T05:01:39Z","timestamp":1789102899000},"page":"2755-2764","source":"Crossref","is-referenced-by-count":0,"title":["Ultramutagenesis through Combined Msh2 Depletion and Proofreading-Deficient DNA Polymerase \u03b5 Expression Enhances Small-Molecule Target Identification in Forward Genetic Screens"],"prefix":"10.1021","volume":"21","author":[{"given":"Alexander-Hoi","family":"Nguyen","sequence":"first","affiliation":[{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75390"]},{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75390"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicky","family":"Li","sequence":"additional","affiliation":[{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75390"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Min","family":"Chen","sequence":"additional","affiliation":[{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75390"]},{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75235"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Kimberg","sequence":"additional","affiliation":[{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75390"]},{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75390"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Davis","sequence":"additional","affiliation":[{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75390"]},{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75235"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8466-2199","authenticated-orcid":true,"given":"David G.","family":"McFadden","sequence":"additional","affiliation":[{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75390"]},{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75390"]},{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75390"]},{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75235"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8384-6540","authenticated-orcid":true,"given":"Juan Manuel","family":"Povedano","sequence":"additional","affiliation":[{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75390"]},{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75390"]},{"name":"UT Southwestern Medical Center , , , ,","place":["Dallas, Texas, United States, 75235"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"issue":"4","key":"2026101523062813300_cit1","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/nchembio.1199","article-title":"Target identification and mechanism of action in chemical biology and drug discovery","volume":"9","author":"Schenone","year":"2013","journal-title":"Nat. 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Biol."},{"issue":"11","key":"2026101523062813300_cit6","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1016\/j.chembiol.2023.07.017","article-title":"Inducible mismatch repair streamlines forward genetic approaches to target identification of cytotoxic small molecules","volume":"30","author":"Nguyen","year":"2023","journal-title":"Cell Chem. Biol."},{"issue":"8","key":"2026101523062813300_cit7","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1016\/j.chembiol.2022.06.002","article-title":"TK216 targets microtubules in Ewing sarcoma cells","volume":"29","author":"Povedano","year":"2022","journal-title":"Cell Chem. 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