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Inhibition of TS disrupts the dUTP:dTTP balance, leading to uracil misincorporation, triggering futile base excision repair cycles, DNA strand breaks, and ultimately cell death. Interestingly, when the main uracil-DNA repair pathway is inhibited, treatment with TS-inhibitory drugs still leads to cell death. Beyond its catalytic role, TS also binds RNA, autoregulating its own translation and interacting with transcripts such as p53 and c-Myc, thereby linking TS activity to broader post-transcriptional regulatory networks. These interactions, together with regulation by miRNAs and lncRNAs, suggest that TS inhibition may provoke cellular responses extending beyond DNA metabolism. To explore these mechanisms, we investigated the transcriptomic effects of TS inhibition with either 5FdUR or RTX in wild-type HCT116 and two HCT116-derived cell lines with different capacities in base excision and mismatch repair pathways. Both drugs induced DNA damage responses yet displayed distinct transcriptional signatures. A strong 5FdUR-biased induction of mRNAs corresponding to p53-related pathways was detected in all cell lines and further validated with qPCR and Western blot. Moreover, co-immunoprecipitation coupled to sequencing revealed direct RNA partners of TS, highlighting its possible post-transcriptional regulatory role. Our findings underscore the multifaceted impact of TS inhibition, linking enzymatic disruption to RNA-level regulation and revealing drug-specific differences in cellular responses.<\/jats:p>","DOI":"10.1371\/journal.pone.0332491","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T17:46:28Z","timestamp":1782927988000},"page":"e0332491","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thymidylate synthase inhibitory drugs induce p53-dependent pathways differently"],"prefix":"10.1371","volume":"21","author":[{"given":"Eszter","family":"Holub","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milda Blanka","family":"Szajk\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Felf\u00f6ldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Be\u00e1ta G.","family":"V\u00e9rtessy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2294-3002","authenticated-orcid":true,"given":"Ang\u00e9la","family":"B\u00e9k\u00e9si","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"pone.0332491.ref001","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.mam.2016.11.005","article-title":"Targeting nuclear thymidylate biosynthesis","volume":"53","author":"J Chon","year":"2017","journal-title":"Mol Aspects Med"},{"issue":"5","key":"pone.0332491.ref002","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/nrclinonc.2014.51","article-title":"Standing the test of time: targeting thymidylate biosynthesis in cancer therapy","volume":"11","author":"PM Wilson","year":"2014","journal-title":"Nat Rev Clin Oncol"},{"issue":"58","key":"pone.0332491.ref003","doi-asserted-by":"crossref","first-page":"8935","DOI":"10.1038\/sj.onc.1205996","article-title":"Uracil in DNA--occurrence, consequences and repair","volume":"21","author":"HE Krokan","year":"2002","journal-title":"Oncogene"},{"issue":"2","key":"pone.0332491.ref004","doi-asserted-by":"crossref","first-page":"191","DOI":"10.2174\/0929867053363432","article-title":"Novel chemical strategies for thymidylate synthase inhibition","volume":"12","author":"WH Gmeiner","year":"2005","journal-title":"Curr Med Chem"},{"issue":"5","key":"pone.0332491.ref005","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1007\/s00018-008-8557-5","article-title":"Participation of DNA repair in the response to 5-fluorouracil","volume":"66","author":"MD Wyatt","year":"2009","journal-title":"Cell Mol Life Sci"},{"issue":"4","key":"pone.0332491.ref006","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1023\/A:1008351221345","article-title":"Downstream molecular determinants of response to 5-fluorouracil and antifolate thymidylate synthase inhibitors","volume":"11","author":"B Van Triest","year":"2000","journal-title":"Ann Oncol"},{"issue":"1517","key":"pone.0332491.ref007","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1098\/rstb.2008.0186","article-title":"Uracil in DNA and its processing by different DNA glycosylases","volume":"364","author":"T Visnes","year":"2009","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"issue":"36","key":"pone.0332491.ref008","doi-asserted-by":"crossref","first-page":"26879","DOI":"10.1016\/S0021-9258(19)74193-3","article-title":"Kinetics of the uracil-DNA glycosylase\/inhibitor protein association. 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