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Previous studies found that KP1019 damages DNA in both cancer cells and the budding yeast Saccharomyces cerevisiae. To identify other potential targets of KP1019 along with pathways that modulate the drug\u2019s cellular effects, we screened the yeast gene deletion strain library by quantitative high-throughput cell array phenotyping (Q-HTCP). Fitness differences, as judged by growth curve analysis, identified genes for which loss of function (gene deletion) interacts with (enhances or suppresses) KP1019 effects. Drug-enhancing deletions were enriched for DNA repair functions, consistent with DNA damage being a primary target of KP1019 in yeast. pH homeostasis also modified the effects of KP1019. Drug-suppressing deletions prominently involved ribosomal proteins. A mechanistic link between ribosomal protein function and KP1019 toxicity was supported by dose-dependent accumulation of Rpl7a-GFP in the nucleolus, which is a hallmark of ribosomal biogenesis stress. Furthermore, KP1019 acted synergistically with the TOR pathway inhibitor everolimus to inhibit cell proliferation. The resulting model, wherein KP1019 perturbs ribosome assembly, can inform the design of future combination therapies.<\/jats:p>","DOI":"10.3390\/ijms27073275","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T02:06:21Z","timestamp":1775441181000},"page":"3275","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Yeast Phenomic Analysis Reveals DNA Repair, pH Homeostasis, and Ribosomal Biogenesis as Modulators of Anticancer Ruthenium Complex KP1019"],"prefix":"10.3390","volume":"27","author":[{"given":"Amanda F.","family":"Bible","sequence":"first","affiliation":[{"name":"Cognitive Neurology, Ochsner Medical Center, New Orleans, LA 70121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5753-2945","authenticated-orcid":false,"given":"Jackson S.","family":"Blackman","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Rodgers","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel R.","family":"Gary","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Colorado, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Rainey","sequence":"additional","affiliation":[{"name":"Department of Biology, Rhodes College, Memphis, TN 38112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0140-6788","authenticated-orcid":false,"given":"Mary E.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Biology, Rhodes College, Memphis, TN 38112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Stepanov","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1176-6469","authenticated-orcid":false,"given":"John L.","family":"Hartman 4th","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2901-5949","authenticated-orcid":false,"given":"Laura K.","family":"Stultz","sequence":"additional","affiliation":[{"name":"Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9312-1682","authenticated-orcid":false,"given":"Pamela K.","family":"Hanson","sequence":"additional","affiliation":[{"name":"Department of Biology, Furman University, Greenville, SC 29613, USA"},{"name":"Department of Clinical and Diagnostic Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"14298","DOI":"10.1073\/pnas.162491399","article-title":"Uptake of the Anticancer Drug Cisplatin Mediated by the Copper Transporter Ctr1 in Yeast and Mammals","volume":"99","author":"Ishida","year":"2002","journal-title":"Proc. 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